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I. Origin of the germ line.

Studies of the mechanisms that underlie human gametogenesis provide a basis for understanding
chromosome anomalies, contraceptive techniques, and assisted reproduction.
A. Migration of the primordial germ cells.
Cells that give rise to the gametes originate within the primary ectoderm during the second
week of development. They then detach from the ectoderm and migrate into the yolk sac.
At first they are seen as a mass of extraembryonic mesoderm at the caudal end of the embryo
and then within the endoderm of the yolk sac. These cells are called the primordial germ cells,
and their lineage constitutes the germ line.
B. During the fourth week, the primordial germ cells migrate into the posterior body wall of the embryo
from the yolk sac.
The primordial germ cells continue to multiply by mitosis during their migration.
In the dorsal body wall, these cells come to rest on either side of the midline in the loose
mesenchymal tissue adjacent to the tenth thoracic vertebrae level that will form the gonads.
The germ cells then induce the adjacent coelonic epithelium and mesonephros to proliferate
and form the primitive sex cords. This creates a swelling (genital ridges/primordial gonads)
medial to each mesonephros on either side of the vertebrae column.
Teratoma: stray germ cells can get stranded along the route of migration at inappropriate sites
in the dorsal body wall. These cells can eventually give rise to a tumor.
Cortical sex cords nourish and regulate the development ovarian follicles in females.
Medullary sex cords nourish and regulate the development of the sertoli cells in males.

II. Gametogenesis.

The process of meiosis and cytodifferentiation converts germ cells into mature male and female
gametes.

A. Spermatogenesis.

At puberty, the testes begin to secrete greatly increased amounts of testosterone. This triggers
maturation of the seminiferous tubules, and the commencement of spermatogenesis.
Primordial germ cells resume development and divide several times by mitosis, producing
spermatogonia.
Migratory phase primary spermatocytes 1st meiotic divisions two secondary spermatocytes 2nd
meiotic division 4 spermatids.
Spermiogenesis: tubulobulbar complexes transfer excess cytoplasm to the sertoli cells, causing
changes in shape and internal organization that transform them into spermatozoa.
Spermiation : last connections with sertoli cells break, releasing the spermatozoa into the tubule
lumen.
Capacitation: the final step of sperm maturation takes place in the female genital tract and
requires contact with the secretions of the oviduct. Spermatozoa used in in-vitro fertilization
procedures are artificially capacitated.

Summary:
spermatogenesis 64 days:
16 days for sprematogonial mitosis
8 days for 1st meiotic division
16 days for 2nd meiotic division
24 days for spermiogenesis final step is capacitation

Clinical Note: Offspring of older men have an increased incidence of achondroplasia (a congenital
skeletal anomaly characterized by retarded bone growth).

B. Oogenesis is discontinuous and begins during fetal life.


At 5 months of fetal life the total number of primary oocytes have been produced in the ovaries.
12 weeks development a proportion of the several million oogonia in the genital ridges enters
the first meiotic prophase and then almost immediately becomes dormant. The follicle cells
derived from the sex cord cells enclose the primary oocyte, constituting the primordial follicle.
By puberty only 400,000 of 7 million remain.
Female puberty the rising levels of pituitary gonadotropins (FSH + LH) regulate later phases of
folliculogenesis in the ovary and the proliferative phase in the uterine endometrium.
5-12 primary oocytes become growing follicles. Some of the growing follicles degenerate while
others continue to respond to the rising level of FSH by taking up fluid and developing a central

fluid filled cavity called the antrum. Thus it is now called an antral follicle. Eventually one of the
growing follicles gains primacy while the others degenerate. The mature graafian follicle
continues to enlarge by absorbing fluid, but at this point the oocyte still has not resumed
meiosis.
The ovulatory surge (about day 15 or 14 of the menstrual cycle) of FSH + LH stimulates the
primary oocyte of the remaining mature graafian follicle to resume meiosis. The cell division
forms the secondary oocytes and the first polar body.
The secondary oocyte promptly beings the second meiosis division, but is arrested at the second
meiotic metaphase (about 3 hours before ovulation).
Ovulation occurs about 38 hours after the beginning of the ovulatory surge of FSH and LH. A
combination of tension produced by smooth muscle cells in the follicle wall, plus the release of
collagen-degrading enzymes, cause the follicle to rupture in a non-explosive process.
Subsequently, the sticky mass formed by the oocyte and cumulus is actively scraped off the
surface of the ovary by the fimbriated mouth of the oviduct. The beating cilia move the oocyte
to the ampulla of the oviduct.
The oocyte is viable for as long as 24 hours. (Clinical side bar: prevention of ovulation with
progesterone interferes with the release of FSH and LH).

Clinical Note:
Since all of the primary oocytes are formed by month 5 of fetal life the incidence of trimsomy 21 (Down
Syndrome) increases with advanced age of the mother.

C. Chromosomal anomalies that arise during gametogenesis.


1/3 of all conceptions in healthy women abort spontaneously. Chromosomal anomalies cause
about 40% to 50% of them.
The chromosomal anomalies that allow embryos to survive result in infants with a variety of
disorders such as Down Syndrome.
Abnormal chromosomes can be produced by an error in meiosis, fertilization, or mitosis. The
gametes or blastomeres that result from these errors contain missing or extra chromosomes, or
chromosomes with duplicated, deleted, or rearranged segments.
Monosomy: results from the fusion of a normal gamete with another that is missing a specific
chromosome.
Example: monosomy 21 these embryos die rapidly during embryonic
development.
Trisomy: results from the fusion of a normal gamete with another that has two of the same kind
of chromosome. Trisomy 21, Down Syndrome, results in individuals that exhibit congenital heart
defects, mental retardation, and propensity to development leukemia. 95% of Down Syndrome
arises through nondisjunction in that maternal germ line. Can an individual with Down
Syndrome produce normal offspring? Yes, meiosis of a trisomic germ cell yields gametes with a
normal single copy of the chromosome as well as abnormal gametes with two copies.

III. Fertilization and first days of development

A. Fertilization (occurs in the ampulla of the uterine tube):


Sperm binding occurs through the interaction of sperm glycosyltransferases and the ZP3
receptors located on the Zona Pellucida
The fusion of the spermatozoon cell membrane (aided by acrosomal enzymes!acrosin)
with the oocyte membrane causes the mechanism (cortical reaction) that prevents
polyspermy, as well as causing the oocyte to resume meiosis. The sperm mitochondria
and tail degenerate.
The secondary oocyte completes the second meiotic metaphase and anaphase
producing another polar body. The first polar body simultaneously completes its second
meiotic division. The oocyte is now considered to be a definitive oocyte.
The female and male pronuclei fuse, forming the diploid and 2N nucleus of the fertilized
zygote. This is the zero time point of embryonic development.Ploidy refers to the
number of copies of each chromosome present in the nucleus. N number refers to the
number of copies of each unique double- stranded DNA molecule in the nucleus. Clinical
side bar: antiprogesterone compound RU-486 is an abortifacient.
B. First days of development.
As the zygote travels down the oviduct it undergoes cleavage without increasing its size. This subdivides
the large zygote into many smaller daughter cells called blastomeres.
24 Hours: First cleavage.
48 Hours: Second cleavage
3 Days: Embryo consists of 6 to 12 cells, reorganization (compaction!Uvomorulin, a glycoprotein
found on the surface of blastomeres, is involved in compaction) of the blastomeres, starts at the
8 cell stage. The centrally placed blastomeres are now called the inner cell mass (they give rise
to most of the embryo proper, which is also called the embryoblast). The blastomeres at the
periphery constitute the outer cell mass, they are the primary source for the membranes of the
placenta. It is also refered to as the trophoblast.
4 Days: Embryo consists of 16 to 32 cells called morula.
5 Days: The embryo is now called a blastocyst. A large cavity called the blastocyst cavity forms
due to the hydrostatic pressure. The embryoblast cells form a compact mass at one side of the
cavity (embryonic pole), while the trophoblast is organized into a thin, single-layered epithelium
6 Days: Blastocyst implants into the uterine wall (Fig 1-13). The blastocyst hatches from the
zona pellucida before implanting. The trophoblast at the embryonic pole differentiates to
produce the syncytiotrophoblast, and begins to implant the blastocyst into the uterine
endometrium.

Some of the proliferating trophoblast cells lose their membranes and form a syncytium. The
trophoblast cells, which form the wall of the blastocyst, retain their cell membranes and
constitute the cytotrophoblast.
Ectopic pregnancy results when a blastocyst implants in the peritoneal cavity on the surface of
the ovary, within the oviduct, or at an abnormal site in the uterus. Because the blood vessels at
abnormal implantation sites are apt to rupture, ectopic pregnancy is often revealed by
symptoms of abdominal pain and/or vaginal bleeding.

Week two
I. Days 8-9
The embryoblast consists of an external layer called the epiblast (primary ectoderm) and an
internal layer called the hypoblast (primary endoderm). The resulting two-layered embryoblast
is called the bilaminar germ disc.
As implantation progresses, the expanding syncytiotrophoblast gradually envelops the
blastocyst.
A layer of epiblast cells is gradually displaced toward the embryonic pole by accumulating fluid.
These cells differentiate into amnioblasts, which form the amniotic membrane. The newly
formed cavity is called the amnion.
Cells at the periphery of the hypoblast begin to migrate out over the inner surface of the
cytotrophoblast. Eventually, these migrating hypoblast cells completely line the former
blastocyst cavity.
II. Days 10-15
This new membrane is now called the exocoelomic membrane or Heusers membrane
The former blastocyst cavity is now called the primary yolk sac or exocoelomic cavity
Once the primary yolk sac is formed, a thick, loosely reticular layer of cellular material called the
extraembryonic reticulum is secreted between Heusers membrane and the cytotrophoblast.
Extraembryonic mesoderm cells that arise from the epiblast at the caudal end of the bilaminar
germ disc begin to migrate out. Two layers result--one coating the outer surface of Heusers
membrane and the other lining the inner surface of the cytotrophoblast
Eventually the extraembryonic reticulum trapped between the two layers of extraembryonic
mesoderm breaks down and is replaced by fluid, forming the chorionic cavity
The growth and migration of the extraembryonic mesoderm gradually separates the amnion
from the cytotrophoblast
On day 12, a second wave of proliferation in the hypoblast produces a new membrane that
migrates out over the inside of the extraembryonic mesoderm, pushing the primary yolk sac in
front of it. This new layer becomes the endodermal lining of the definitive (secondary) yolk sac
As the definitive yolk sac develops on day 13 the primary yolk sac breaks up into disintegrating
exocoelomic vesicles

By 14-15 days the bilaminar germ disc has formed and is suspended in the chorionic cavity by a
thick connecting stalk.
The extraembryonic mesoderm forming the outer layer of the yolk sac wall is a major site of
hematopoiesis. Cells from the primary ectoderm migrate into the yolk sac forming the first
endothelial cells and hematopoietic stem cells. The coordinated development of these cells into
the vitelline vasculature is called blood island formation.
Meckels diverticulum: The yolk sac normally disappears before birth, but if it persists a digestive
tract anomaly may develop.
III. Uteroplacental circulatory system (9-21 days)
The uteroplacental circulation is the system by which maternal and fetal blood flowing through
the placenta come into close contact and exchange gases and metabolites by diffusion.
The system starts to form on day 9 as the trophoblastic lacunae open within the
synctiotrophoblast. Eventually, they anastomose (blood vessels join either end- to-end or sideto-side) with maternal capillaries.
By days 11 and 13 extensions of cytotrophoblast grow out into the blood-filled lacunae, carrying
with them a covering of syncytiotrophoblast, forming the primary stem villi.
On day 16 the extraembryonic mesoderm associated with the cytotrophoblast penetrates the
core at the primary stem villi. The resulting villi are now called secondary stem villi.
By 21 days the tertiary stem villi have formed. The villous mesoderm has given rise to blood
vessels that connect with the vessels forming in the embryo proper. This establishes the working
uteroplacental circulation.
IV. Clinical Applications
A. Human chorionic gonadotropin (hCG):
is produced by the syncytiotrophoblast.
enters maternal blood circulation.
prevents degeneration of the corpus luteum and stimulates production of progesterone.
can be assayed in maternal blood at day 8 after fertilization and in maternal urine at day
10. This is the basis of early diagnosis of pregnancy.

B. Oncofetal antigens:
are cell surface antigens that normally appear only on embryonic cells but for unkown
reasons reexpress themselves in human malignant cells.
Monoclonal antibodies directed against these antigens is an avenue for cancer therapy.
Examples: Carcinoembryonic antigen (CEA) is associated with colorectal carcinoma.
Alpha-fetalprotein is associated with hepatoma and germ cell tumors.

C. RU-486 (Mifepristone):
will initiate menstruation when taken within 8-10 weeks of the previous menses.
The conceptus will be sloughed along with the endometrium
Is used in conjunction with prostaglandin and is 96% effective at terminating pregnancy.

D. Complete hydatidiform mole:


a pregnancy without an embryo. The conceptus consists only of placental
membranes. A normal diploid karyotype is observed, but all the chromosomes
are derived from the father.
If they do not abort symptoms of hypertension, edema, and vaginal bleeding
may exist in the mother.
Mole remnants are readily diagnosed on the basis of an abnormally high level of
plasma human chorionic gonadotropin (hCG).
Persistent trophoblastic disease: mole remnant grows to form a tumor. These
can also turn into a metastatic choriocarcinoma.

E. Partial hydatidiform moles.


Triploid, with a double dose of paternal chromosomes.
Symptoms are milder and slower to develop.
Tumors that arise are usually benign.

F. Genomic Imprinting:
Cytogenetic analysis of hydatidiform moles suggests that the paternal genetic
complement is responsible for the early development of the placenta and that the
maternal genetic complement is responsible for the early development of the embryo.
These roles were studied using mouse oocytes that contain either two male or two
female pronuclei.
Methylation of DNA is a mechanism that leads to the independent expression of
maternal and paternal genomes during early development. The female germ line is
more highly methylated than the DNA of the male germ line. The methylation of some
genes (such as, H19, IGF2, IGF2r, MASH2, WT1) may lead to their silencing while others
may be activated by methylation.
The pattern of inheritance of a deletion in a specific region of a human chromosome
(15) causes Prader-Willi Syndrome (floppy (hypotonic) infants, low IQ, limb defects,
uncontrollable hunger and subsiquent morbid obesity) when the chromosome is
inherited from the father. But causes a phenotypically distinct condition, Angelman

Syndrome (low IQ, seizures, protruding tungue, and excessively happy), when the
chromosome is inherited from the mother.
The severity and age of onset of several genetic diseases (such as, Huntington's, Chorea,
Nf I and NF II, Wilm's tumor, Beckwith-Wiedemann Syndrome, spinocerebellar ataxia,
myotonic dystrophy) differ depending on the parent from whom the mutated gene is
inherited.

Week Three
Gastrulation & Neurulation

I. Gastrulation and the initial development of the somites and neural tube.

A. Primitive Streak.
Between days 15 and 16 the primitive streak forms. It starts out as a faint groove at the
caudal end of the bilaminar germ disc. Eventually it deepens forming a primitive groove
with a depression (primitive pit) at the cranial end. The mound of epiblast cells
surrounding the pit is called the primitive node.
The fundamental cranial/caudal, left/right, and ventral/dorsal axes are established at
this time.
B. Formation of definitive endoderm and intraembryonic mesoderm (process of gastrulation).
On day 16, epiblast cells near the primitive streak proliferates and migrates through the
primitive streak into the space between the epiblast and hypoblast. Some of the cells
displace the entire hypoblast forming a new layer called the definitive endoderm. It
gives rise to the lining of the future gut and gut derivatives
Other epiblast cells diverge into the space between the epiblast and the nascent
definitive endoderm to form a third layer, the intraembryonic mesoderm
Mesoderm cells that ingress through the primitive node migrate cranially to form the
prechordal plate and notochordal process. The notochordal process is initially formed
as a hollow mesodermal process and then transformed into a solid notochord between
days 16 and 22. During the transformation period the notochord process fuses with the
endoderm. This allows the yolk sac cavity to transiently communicate with the amniotic
cavity through an opening at the primitive pit called the neurenteric canal. During the
transformation process, some cells of endodermal origin may become incorporated into
the notochord.
Mesoderm cells that ingress through the primitive groove migrate to form the
mesoderm lying on either side of the midline.

The epiblast at this point takes on a new name, the ectoderm. Thus all three layers of
the trilaminar germ disc (the ectoderm, mesoderm and definitive endoderm) were
formed from the epiblast.
The buccopharyngeal membrane breaks down eventually to form the opening to the
oral cavity, while the cloacal membrane disintegrates to form the openings of the anus
and the urinary and genital tracks.
C. Paraxial, intermediate, and lateral plate mesoderm.
As the primitive streak regresses, the mesoderm cells that migrated laterally begin to
form cylindrical structures called the paraxial, intermediate and lateral plate mesoderm
on either side of the notochord.
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The fist 7 somitomeres do not go on to form somites. Instead, they give rise to the
muscles of the face, jaw, and throat.
Intermediate Mesoderm: Give rise to urinary system and genital system.
Lateral Plate Mesoderm splits into the splanchnopleuric mesoderm (sometimes refered
to as intraembryonic visceral mesoderm!becomes the mesothelial covering of the
visceral organs) and somatopleuric mesoderm (sometimes refered to as intraembryonic
somatic mesoderm!gives rise to the lining of the body wall, parts of the limbs, and
dermis).
D. Induction of the neural plate.
The axial mesoderm (prechordal and notochordal plate) induces the overlying ectoderm to form
the neural plate.
Formation of the neural tube begins on day 22 at the level of the first five somites.
Closure of the cranial neuropore is bidirectional, and final closure occurs in the area of the
future forebrain.
Closure of the caudal neuropore is craniocaudal and finishes at the level of the second sacral
segment (the level of somite 31).
During neurulation neural crest cells begin to migrate in a craniocaudal wave (beginning on day
22). Cephalic neural crest cells detach and migrate before closure of the cranial neural tube. In
contrast, trunk neural crest cells detach as the lateral lips of the neural tube fuse.
Neural crest cells are an extremely important population of cells that migrate into the embryo to
form a variety of structures.For example: Odontoblasts arise from the neural crest. Neural crest
cells that give rise to Odontoblasts stop migrating and settle down against the buccal epithelium
at locations of the future teeth. Teeth are composite structures made up of the outer white
enamal which covers the teeth above the gums and the inner dentine, a different mineralized
tissue forming the root and interior of the teeth. Dentine and enamel are extracellular products
of two different types of cells, the ameloblasts (enamel) and odontoblasts (dentine).

E. Clinical Applications.
Many of the malformations (like Sirenomelia) of caudal dysplasia seem to be related to
the defects in the growth and migration of mesoderm during the third week
(gastrulation).
The short-tail brachyuric and tailless anuric mouse mutants display a range of
mesodermal defects and disruptions of gastrulation and notochord development that
are very similar to the abnormalities observed in human caudal dysplasia. The
expression of the T gene protein in the primitive streak and gastrulation mesoderm
makes it clear how a mutation in the gene could cause severe caudal dysplasia.
Malformations of neural tube closure:
(1) Spina Bifida Occulta: The mildest form of spina bifida may occur anywhere along the
spinal cord, but is most common at lower lumbar and sacral levels. The vertebral arches
of a single vertebra fail to fuse while the underlying neural tube differentiates normally
and does not protrude from the vertebral canal .
(2) Meningomyelocele: More severe cases of spina bifida result in the protrusion of neural
tissue and meninges.
(3) Anencephaly: This defect involves only the cranial neural tube and results in an exposed
dorsal mass of undifferentiated neural tissue.
(4) Inionschisis: Failure of the neural tube to properly differentiate and close in the
occipital and upper spinal regions.
(5) Rieger Syndrome: Embryological disturbance of the neural crest ectoderm results in
severe enamel hypoplasia, conical and misshapen teeth, hypodontia, hyperdonita, and
impactions. Abnormalities of migration along the buccal epithelium results in ectopism.

1.
2.
3.
4.

1.
2.
3.
4.

Meningohydroencephalocele: This anomaly may form through defective ossification of the


occipital bone (not due to defective NT closure).
Sacrococcygeal teratoma:
the remnants of the primitive streak causes the formation of a tumor.
The tumor is derived from pluripotent cells, thus it contains various types of tissues (bone,
nerve, hair,)
Occurs more commonly in female infants
Becomes malignant during infancy and must be removed by age 6 months
Chordoma:
The remnants of the notochord causes the formation of a tumor.
Found either intracranially or in the sacral region.
More common in men (age 50)
Either benign or malignant.

Musculoskeletal System

I. Role of somites in the formation of the vertebrae and musculature of the developing embryo.

A. Somites subdivide into three kinds of mesodermal primordium (Fig 4-1 and 4-6).

1. Dermatomes: form the dermis of the scalp, neck and trunk.

2. Myotomes: form the segmental musculature of the back and the anterolateral body wall.

3. Sclerotomes: surround the notochord and neural tube and eventually form the vertebral bodies and
vertebral arches and also contribute to the base of the skull. The costal processes that appear on the
vertebral bodies in the thoracic region
go on to form the ribs.

Defective induction of vertibral bodies on one side of the body may result in what medical condition?

II. Vertebral Column.

A. Vertebrae in general.

1. Mesodermal cells from the sclerotome migrate and condense around the notochord to form the
centrum, around the neural tube to form the vertebral arches, and in the body wall to form the costal
processes .

2. Centrum forms the vertebral body.

3. Vertebral arches form the pedicles, laminae, spinous process, articular processes, and the transverse
processes.

4. Costal processes form the ribs.

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B. Intersegmental position of the vertebrae (Fig 4-2, and Fig 4-3).

1. As mesodermal cells from the sclerotome migrate towards the notochord and neural tube, they split
into a cranial portion and a caudal portion.

2. The caudal portion of each sclerotome fuses with the cranial portion of the succeeding sclerotome,
which results in the intersegmental position of the verebra.

3. The splitting of the sclerotome is important because if allows the developing spinal nerve a route of
access to the myotome that it must innervate.

C. Joints of the vertebral column.

1. Synovial joints.

a) Located in the occipital and upper cervical vertebra.

2. Secondary cartilaginous joints (symphyses) (Fig 4-4).

a) Are the joints between the vertebral bodies in which the intervertebral disks
play a role.

b) An intervertebral disk consists of a Nucleus pulposus and an Annulus fibrosus.

c) The Nucleus pulposus is a remnant of the embryonic notochord. By 20 years of age, all notochordal
cells have degenerated such that all notochordal vestiges in the adult are limited to just a noncellular
matrix.

d) The Annulus fibrosus is an outer rim of fibrocartilage derived from mesoderm found between the
vertebral bodies.

D. Clinical Applications.

1. Intervertebral disk herniation is a prolapse of the nucleus pulposus through the defective annulus
fibrosus into the vertebral canal. The nucleus pulposus impinges on spinal roots and results in root pain.

2. Spina bifida occulta (as mentioned in the previous lecture) results from failure of the vertebral arches
to form or fuse.

3. Spondylolisthesis occurs when the pedicles of the vertebral arches fail to fuse with the vertebral
body.

4. Hemivertebrae occurs when wedges of vertebrae appear that are usually situated laterally between
two other vertebrae.

5. Vertebral bar results when there is a localized failure of segmentation on one side of the column,
usually in a posterolateral site.

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6. Block vertebra results when there is a lack of separation between two or more vertebrae, usually
occurring in the lumbar region.

7. Cleft vertebra occurs when a cleft develops in the vertebra, usually in the lumbar region.

8. Idiopathic scoliosis is a lateral deviation of the vertebral column (both deviation and rotation of
vertebral bodies).

E. Ribs.

1. Ribs develop from costal processes, which form at all vertebral levels. However, only costal
processes in the thoracic region grow into ribs.

2. The first seven ribs connect ventrally to the sternum via the costal cartilages and are called the true
ribs. The five lower ribs do not articulate directly with the sternum and are called false ribs (Fig 4-5).

3. Clinical note: Acessory lumbar ribs are the most common. Acessory cervical ribs are attached to the
C7 vertebrae and may put pressure on the lower trunk of the brachial plexus and subclavian artery,
causing superior thoracic outlet syndrome.

F. Sternum.

1. The sternum develops from two sternal bars that form in the ventral body wall independent of the
ribs and clavicle.

2. The sternal bars fuse with each other in a cranial-caudal direction to form the manubrium, body, and
xiphoid process (does not ossify until birth) (Fig 4-5).

3. Clinical note: A sternal cleft occurs when the sternal bars do not fuse completely. It is fairly common
and if small is generally of no clinical significance.The Pectus excavatum (funnel chest) is the most
common chest anomaly consisting of a depression of the chest wall. These individuals demonstrate
cardiopulmonary restriction, drooped shoulders, and scoliosis. Surgical intervention is usually required.

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III.

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Skeletal Muscle.

A. Head and neck musculature.

1. Is derived from somitomeres 1-7 of the head and neck region which participate in the formation of
the pharyngeal arches.

2. Extraocular muscles are derived from somitomeres 1,2,3, and 5. Somitomeres


1,2, and 3 are called preotic myotomes (somites).

3. Tongue muscles are derived from the myotomes in the occipital region.

B. Trunk musculature.

1. Is derived from myotomes in the trunk region that partition into dorsal epimeres and ventral
hypomeres (Fig 4-6).

2. Epimeres develop into the intrinsic back muscles (erector spinae).

3. Hypomeres develop into the prevertebral, intercostal, and abdominal muscles.

IV.

Limb Skeleton and Musculature Development.

A. Inductive interactions that form the limb.

1. Somites induce the formation of limb buds in the somatopleuric lateral plate mesoderm.

!24 days: the upper limb bud appears in the lower cervical region (Fig 11-1A&B).

!28 days: the lower limb bud appears in the lower lumbar region.

2. Apical ectodermal ridge induces the differentiation of the limb buds (Fig 111C&D).

3. The late-formed mesenchyme at the tip of the limb bud differentiates into the distal segments of the
limb (Fig 11-2).

4. The early-formed mesenchyme at the base of the bud differentiates into the proximal segments of
the limb (Fig 11-2).

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B. Differentiation of the limb bud (5th to 8th weeks of development) (Fig 11-3).

The upper limbs develop in advance of the lower limbs, but by the end of limb development the two
limbs are nearly synchronized.

Day 33! Upper limb: hand plate, fore-arm, arm, and shoulder regions can be distinguished.

Lower limb: the tappering distal tip (eventually forms the foot) can be distinguished.

Day 37! Upper limb: carpal region and digital plate have formed in the hand plate.

Lower limb: thigh, leg, and foot have become distinct.

Day 38! Upper limb: the tips of the digital rays project slightly, producing a crenulated rim on the digital
plate. Programmed cell death takes place in the radial necrotic zones between the digital rays. This
process will gradually sculpt the digital rays out of the digital plate to form the fingers and toes.

Lower limb: has increased in length and has formed a defined foot plate.

Day 44! Upper limb: the margin of the digital plate is deeply notched and the grooves between the
digital plate is deeper. The elbow has formed.

Lower limb: Toe rays are visible in the digital plate of the foot, but the rim of the plate is not crenulated.

Day 47! Upper limb: has undergone horizontal flexion.

Lower limb: has started to flex and the toe rays are more prominent
(digital plate is still smooth).

Day 52! Upper limb: is slightly bent at the elbows. The fingers have developed distal swellings called
tactile pads. The hands are slightly flexed at the wrists and meet at the midline.

Lower limb: is longer and the feet have begun to approach each other at the midline. The rim of the
digital plate is notched.

Day 56! Upper limb & Lower limb: arms and legs are well defined. The fingers of the two hands overlap
at the midline. Toes are fully developed.

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C. Somite, lateral plate mesoderm, and neural crest contribution to the limb.

1. Lateral plate mesoderm gives rise to the bones, tendons, ligaments, and vasculature of the limbs.

2. Somitic mesoderm that migrates into the developing limb gives rise to the musculature (Fig 11-5).

3. Neural Crest Cells that migrate into the limb give rise to melanocytes and
Schwann cells.

Note: The quail-chick chimera system was used to study the cell populations that give rise to the various
elements of the limbs.

D. The process of endochondral ossification forms the limb bones via a cartilaginous precursor (Fig 116).

1. The axial mesenchymal condensation is a rodlike condensation of lateral plate mesenchyme that
forms along the long axis of the limb bud.

2. Chondrocytes within this region respond to growth factors and begin to differentiate, releasing
extracellular matrix molecules (collagen type II and proteoglycans).

3. The initial phase of chondrification results in the perichondrium. This deposition of cartilage around
the entire axial mesenchymal condensation forms a cartilaginous envelope.

4. The chondrifying bone primordia will go on to form a cartilaginous model of each limb bone while the
mesenchyme of the interzone forms the fibroblastic tissue of the presumptive joint.

5. After the limb bone has chondrified the process of ossification starts in the
primary ossification center.

6. First mesenchymal cells in the perichondrium respond to growth factor-Beta-like molecules and
differentiate into osteoblasts (bone cells). These cells secrete the calcium salt matrix of minearlized
bone, forming a primary bone collar around the circumference of the bone.

7. The osteoclasts break down previously formed bone to remodel the growing limb bones.

8. Eventually even the cartilaginous core enclosed by the primary bone collar also begins to ossify,
forming a loose trabecular network of bone.

9. At birth, the diaphyses (shafts of the limb bones consisting of a bone collar and trabecular core) are
completely ossified, while the end of the bones (epiphyses) are still cartilaginous.

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10. After birth, secondary ossification centers develop in the epiphyses, which gradually ossify.

11. The epiphyseal cartilage plate (growth plate or physis) persists between the epiphysis and the
metaphysis ( the growing end of the diaphysis). The continued proliferation of the chondrocytes allows
the diaphysis to lengthen during development. When the bones have stopped growing the epiphyses
and diaphyses fuse.

E. The timeline of limb bone formation.

1. 5th week! axial mesenchyme of the limb buds begins to condense. The bones of the UPPER LIMB
form slightly earlier than the LOWER LIMB.

2. End of 5th week! the axial mesenchymal condensation that will give rise to
the proximal bones(scapula and humerus in the UPPER LIMB; the pelvic bones and femur in the LOWER
LIMB) is distinct.

3. Early 6th week! the mesenchymal precursor of the distal limb skeleton is distinct in the UPPER AND
LOWER LIMBS, and chondrification commences in the humerus, ulna, and radius.
4. Middle of 6th week! In LOWER LIMB, the femur, the tibia, and, to a lesser extent, the fibula begin to
chondrify.
5. End of 6th week! the carpal and metacarpal bones of the UPPER LIMB and the tarsals and
metatarsals of the LOWER LIMB begin to chondrify.
6. Early 7th week! all the bones of the UPPER LIMB except the distal phalanges of the second to fifth
digits are undergoing chondrification. Primary ossification centers begin to appear. Ossification has
commenced in the clavicle.
7. End of 7th week! the distal phalanges of the HAND and all the bones of the LOWER LIMB (except
the distal row of phalanges) have begun to chondrify. Humerus, radius, and ulna have begun
ossification.
8. 8th week! The distal phalanges of the toes chondrify. Ossification begins in the femur and tibia.
9. 9th week! The scapula and ilium begin to ossify.
10. 10th-14th weeks! Metacarpals, metatarsals, distal phalanges, proximal phalanges, and middle
phalanges begin to ossify.
11. 15th week! The ischium begins to ossify.
12. 16th week! Ossification of the calcaneus begins.
13. 20th week! The pubis begins to ossify.

14. Early Childhood! Smaller carpal and tarsal bones finally ossify.

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Note: Intramembranous ossification occurs in the embryo when mesoderm condenses into sheets of
highly vascular connective tissue, which then directly forms a primary ossification center. The frontal
bone and the parietal bones are examples of bones that undergo intramembranous ossification. All
bones of both the Upper and Lower limbs undergo endochondral ossification. The clavicle, however,
undergoes both membranous and endochondral ossification.

F. Development of the diarthrodial (synovial) joints connecting the limb bones (Fig
11-6).

1. First, as mentioned earlier, the mesenchyme of the interzones between the chondrifying bone
primordia differentiates into fibroblastic tissue (undifferentiated connective tissue).

2. The fibroblastic tissue of the presumptive joint differentiates into three layers: a cartilage layer at the
outer end of the future joint, and a central layer of dense connective tissue. The central layer gives rise
to the internal elements of the joint.

3. The central layer condenses at the proximal and distal regions to form the
synovial tissue. This will eventually line the joint cavity.

4. The central zone of the central layer gives rise to the menisci and to enclosed joint ligaments.

5. Vacuoles appear within the central zone, eventually coalescing to form the synovial cavity. The joint
capsule arises from the mesenchymal sheath surrounding the entire interzone.

Note: The synchondroidal joints of the pelvis bones develop from interzones, but the interzone
mesenchyme simply differentiates into a single layer of fibrocartilage.

G. Limb musculature development.

1. During the fifth week, somitic mesoderm invades the limb bud and forms two large condensations,
one dorsal to the axial mesenchymal column and one ventral to it (Fig 11-7).

2. The cells of the condensations differentiate into myoblasts (muscle cell precursors).

3. The dorsal muscle mass gives rise to the extensors and supinators of the
UPPER limb and to the extensors and abductors of the LOWER limb.

4. The ventral muscle mass gives rise to the flexors and pronators of the UPPER limb and to the flexors
and adductors of the LOWER limb. Note: Some muscles migrate from their site of origin and acquire
different functions.

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H. Rotation of the limbs (Fig. 11-10).

1. The upper limbs.

a) They appear in week 4 as small bulges oriented in a coronal plane.

b) They undergo a horizontal flexion in week 6 so that they are now oriented in a parasagittal plane.

c) They rotate laterally 90 degrees during weeks 6 to 8 so that the elbow points posteriorly, the
extensor compartment lies posterior, and the flexor compartment lies anterior.

d) The 90 degree lateral rotation of the upper limb bud causes the originally straight segmental pattern
of innervation to twist into a spiral in the adult.

2. The Lower limbs.

a) They ppear in week 4 (about 4 days after the upper limb bud) as small bulges oriented in a coronal
plane.

b) They undergo horizontal flexion in week 6 so that they are now oriented in a parasagittal plane.

c) They rotate medially 90 degrees during weeks 6 to 8 so that the knee points anteriorly, the extensor
compartment lies anteriorly, and the flexor compartment lies posterior.

d) The rotation causes the originally straight segmental pattern of innervation to become twisted in a
spiral in the adult.

3. Final anatomic situation of the limbs.

a) Note that the upper limbs rotate laterally 90 degrees, whereas the lower limbs rotate medially 90
degrees. This sets up the following anatomic situations:

b) Flexior compartment of the upper limb is anterior, whereas the flexor compartment of the lower
limb is posterior.

c) Extensor compartment of the upper limb is posterior, whereas the extensor compartment of the
lower limb is anterior.

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V. Clinical Applications.

A. Congenital Anomalies of the limbs (Table 11-2).

1. Reduction defects:

a) meromelia!part of a limb is missing (Fig 11-11A).

b) Amelia!an entire limb is missing (Fig 11-11B).

c) Ectrodactyly!Absense of any number of fingers or toes. d) Adactyly!Absense of all the digits on a


limb.
2. Duplication defects: supernumerary limb elements. a) Polydactyly!extra digits (Fig 11-11C).
3. Dysplasia!malformation of the limbs:

a) Syndactyly!fusion of digits (Fig 11-12 & 11-14).

b) Gigantism (Acrodolichomelia)!excessive growth of parts of the limb. c) Phocomelia!Short, ill-formed


upper or lower limbs.
d) Hemimelia!Stunting of distal limb segments.

B. General causes of limb defects.

1. Arrest of development

2. Failure of differentiation

3. Duplication

4. Overgrowth

5. Hypoplasia

6. Focal Defects

7. General skeletal abnormalities that indirectly effect limb development.

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C. Etiology of limb defects. Genetic or teratogenic (Environmental)? Note: Most human limb defects
appear to have a mulifactorial etiology, arising from an interaction between environmental factors and
the individual's genetic makeup. However, some limbs defects have been attributed to a genetic or an
environmental basis.

1. Genetic basis.

a) Familial associations indicate a genetic basis for some limb anomalies. Both polydactyly and
ectrodactyly often run in families.

b) These defects show an autosomal dominant, autosomal recessive, or X- linked pattern of inheritiance

c) Other limb defects known to be transmitted as autosomal dominant traits include partial tibia defect,
general micromelia, triphalangeal thumbs, lobster claw hand and foot (Fig 11-13), and the Adams-Oliver
syndrome (characterized by limb anomalies and defects of the scalp and skull).

d) An autosomal recessive disease characterized by the fusion of the digits


(syndactyly), results from a mutation of the HOX gene HOXD13 (Fig 1114).Note: Four clusters of Hox genes are expressed in vertebrates.
Members of the most 5' members of the HoxD and Hoxa clusters (Hoxd9-13) are expressed in a distal to
proximal transcriptional cascade within the growing limb bud (Fig 11-21 & Fig 11-22).

e) Chromosomal anomalies!Trisomy 18 causes limb defects.

2. Environmental teratogens. A variety of drugs, metabolic poisons, and other environmental


teratogens have been shown to cause limb defects humans.

a) Agents that influence general cell metabolism or cell proliferation (if taken during the period of limb
morphogenesis).

(1) 5'-fluoro-2-deoxyuridine (an inhibitor of thymidylate synthetase). (2) Acetazolamide (a carbonic


anhydrase inhibitor)
(3) Triethylene melamine (an alkylating agent) (4) Cadmium (zinc metalloenzyme inhibitor)
b) Febrific (Fever-causing) diseases.Hyperthermia is also a significant cause of limb defects. Increases in
body temperature of only 1 to 2.5C can induce limb malformations.

c) Therapeutic drugs that have teratogenic effects.

(1) Aspirin.

(2) Dimethadione (Anticonvulsant)

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(3) Retinoic Acid

(4) Thalidomide (spasmolytic and anticonvulsant under the trade name Contergan). It exerts its effects
only when taken during the sensitive period of limb morphogenesis, between about 4 and 8 weeks.
Thalidomide is thought to disrupt cell adhesion in the limb by downregulating cell surface adhesion
receptors (integrins and selectin) or by inhibiting angiogenesis. Recently, thalidomide has been utilized
in the treatment of autoimmune and inflammatory conditions.Note: The incidence of amelia,
phocomelia, hypoplasia, syndactyly (Fig 11-16) and other embryopathies (anotia and cardiac defects)
exactly paralleled the

West German sales of Thalidomide, with a lag of about 7 to 8 months (Fig


11-15). About 40% of the thalidomide babies died soon after birth.

d) Amniotic bands (Amniotic band syndrome), oligohydramnios


(insufficient amniotic fluid), and local vascular disruption.

(1) Amniotic Band Syndrome. Occasionally, a band of tissue detaches from the amnion and wraps
around part of the embryo, constricting its growth and causing malformations. Amniotic bands may
amputate or constrict a developing limb or may induce facial dysplasia by entangling the head and face
(Fig 11-17).

(2) Constricted Uterine environment (and subsequent compression- induced vascular disruption) cause
limb reduction anomalies.

(a) Oligohydramnios!insufficient amniotic fluid.

(b) Bicornuate Uterus!a Y-shaped uterus resulting from incomplete fusion of the paramesonephric ducts
during formation of the uterovaginal canal.

(c) Large benign tumors of the uterine myometrium

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Heart Development

I. Formation and Folding of the Primitive Heart.

A. Lateral endocardial tubes fuse to form the primary heart tube.

1. Cardiogenic region: a horseshoe-shaped zone of splanchnopleuric mesoderm located cranial and


lateral to the neural plate on the embryonic disc (Fig 7.1A).

2. Vasculogenesis: Late in the third week, the cephalic and lateral folding of the embryo brings the two
lateral endocardial tubes into the thoracic region. Eventually, they meet at the midline and fuse to form
a single tube (Fig 7-2).

Note: The fusion of the two tubes is facilitated by programmed cell death in their contacting surfaces.

B. Formation of the paired dorsal aortae of the primitive circulatory system.

1. The major vessels of the embryo develop at the same time as the endocardial tubes.

2. The inflow and outflow tracts of the future heart make connections with the paired lateral
endocardial tubes even before these tubes are translocated into the thorax and fuse to form the heart
(Fig 7-1 and Fig 7-3).

3. Outflow tract:

a. The paired dorsal aortae forms the primary outflow tract of the heart. As the flexion and growth of
the cephalic fold carries the endocardial tubes first into the cervical and then into the thoracic region,
the cranial ends of the dorsal aortae are pulled ventrally until they form a dorsoventral loop (the first
aortic arch) (Fig 7-3D).

b. During the fourth and fifth weeks four more aortic arches will develop in connection with the
pharyngeal arches (Fig 7-5).

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4. Infow tract:

a. The infow to the heart is initially supplied by six vessels, three on each side
(Fig 7-5).

b. Venous blood from the body of the embryo enters the heart through the common cardinal veins.
They are formed by the fusion of the posterior cardinal veins (drains the trunk) and the anterior cardinal
veins (drains the head region) (Fig 7-5).

c. The vitelline veins drain the yolk sac (Fig 7-5).

d. The umbilical veins deliver oxygenated blood from the placenta to the heart
(Fig 7-5).

C. Subdivsion of the primary heart tube (Fig 7-6).

1. Early in the fourth week (by day 21) sulci and expansions appear in the presumptive heart tube (Fig 76). During the next 5 weeks, these expansions contribute to various heart chanbers.

2. Starting from the inflow end (inferior) working towards the outflow end
(superior):

a) Sinus Venous: consists of the partially confluent left and right sinus horns into which the common
cardinal veins drain.

b) Primitive atrium: gives rise to parts of both atria.

c) Atrioventricular sulcus: separates primitive atrium and ventricle chambers. d) Ventricle: gives rise to
most of the definitive left ventricle.
e) Bulboventricluar or interventricular sulcus: separtes the ventricle and bulbus cordis expansions.

f) Inferior bulbus cordis: forms most of the right ventricle.

g) Superior bulbus cordis or conotruncus: forms the distal outflow regions of the left and right
ventricles, including the conus cordis and the truncus arteriosus.

h) Truncus Arteriosus eventually splits to form the ascending aorta and the
pulmonary trunk. Its superior end is connected to the aortic sac.

i) The aortic sac is continuous with the first aortic arch and, eventually, with the other four aortic
arches.

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D. The four layers of the wall of the primary heart tube (Fig 7-7).

1. Initially the primary heart tube consists of endothelium, but by day 22 the splanchnopleuric
mesoderm invests the fused endocardial tubes and differentiates into two new layers (2 & 3 below).

2. Myocardium (heart muscle)

3. Cardiac Jelly: a thick matrix that is secreted by the developing myocardium.


Thus it separates the myocardium from the fused endocardial tubes.

4. The serous epicardium (visceral percardium) is formed by a population of mesothelial cells that are
independently derived from splanchnopleuric mesoderm.

E. Development of the transverse pericardial sinus (Fig 7-8).

1. The primary heart tube is initially suspended in the primitive pericardial cavity by a dorsal
mesocardium (dorsal mesentery of the heart formed of foregut splanchnopleuric mesoderm).
2. Early in the 4th week the dorsal mesocardium ruptures. The region of the ruptured dorsal
mesocardium becomes the transverse pericardial sinus.

F. Heart tube folding and looping (Fig 7-9).

1. The process of folding and looping establishes the spatial relationships of the future heart chambers
(begins on day 23 and is complete by day 28). Thus, the result of looping is to bring the four
presumptive chambers of the future heart into their correct spacial relation to each other.

2. The bulbus cordis is displaced inferiorly, ventrally, and to the right.

3. The ventricle is displaced to the left.

4. The primitive atrium is displaced posteriorly and superiorly.

Note: Heart looping is a hot topic in basic heart research, but the mechanism is still poorly understood.
Cultured hearts loop correctly even in the absence of the primitive pericardium, cardiac jelly, and blood
flow.

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II. Remodeling of the primitive vasculature.

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A. Shift of venous inflow to the right (no longer bilaterally symetrical).

1. At day 22, the heart and primitive circulatory system are bilaterally symmetrical.

2. The heart starts to beat on day 22, and by day 24 blood begins to circulate throughout the embryo.
At this point, venous return occurs bilaterally from the right and left sinus horns (Fig 7-10A).

3. In the next few weeks the venous system is remodeled so that all the systemic venous blood enters
the right sinus horn via the superior and inferior venae cavae (Fig 7-10B, C).

4. During this shift the left sinus horn ceases to grow and eventually gives rise to the coronary sinus
(drains blood from the coronary circulation of the heart muscle) and the small oblique vein of the left
atrium (Fig 10C).

III. Extensive remodeling of the left and right atria.

A. The right sinus horn is incorporated into the right posterior wall of the primitive
atrium (remodeling of the right atrium).

1. As the right sinus horn and the venea cavae enlarge the right side of the sinus venosus is gradually
incorporated into the right posterior wall of the developing atrium (occurs during the 5th week), giving
rise to the sinus venarum (smooth wall)(Fig 7-11). The sinus venarum eventually gives rise to the
definitive right atrium.

2. The original right half of the primitive atrial wall is displaced ventrally and to the right eventually
giving rise to the right auricle (rough, comblike, trabeculated surface).

3. The process of intussuseption of the right sinus venosus pulls the ostia (openings) of the superior
and inferior venae cavae and future coronary sinus into the posterior wall of the definitive right atrium.
They eventually form the orifices of the superior and inferior venae cavae and the orifice of the coronary
sinus (Fig 7-12).

4. The left venous valve (eventually becomes part of the septum secundium involved in the septation of
the definative right and left atria) and right venous valves (eventually forms the valve of the inferiror
vena cava and the coronary sinus) then form on either side of the three ostia (Fig 7-12).

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B. The trunk of the pulmonary venous system is incorporated into the posterior wall of the left atrium
(Remodeling of the left atrium).

1. Early in the 4th week a single pulmonary vein sprouts from the left side of the primitive atrium and
then branches twice to produce two right and left pulmonary veins (Fig 7-11). These veins anastomose
with veins in the developing bronchial buds.
2. The process of intussuseption, during the 5th week, incorporates the trunk and first two branchings
of the pulmonary vein system into the posterior wall of the left side of the primitive atrium (Fig 7-11 and
Fig 7-12). They form the smooth wall of the definitive left atrium.

3. Thus, the pulmonary venous system opens into the atrium initially through a single large orifice, then
transiently through two orifices, and finally through the four orifices of the definitive pulmonary veins
(Fig 7-13).

IV. Septation of the atria and division of the atrioventricular canal.

A. Septum primum formation.

1. Day 26, a crescent shaped wedge of tissue called the septum primum begins to extend into the
atrium (Fig 7-14).
2. During the 5th week,
atrioventricular canal.

the free edge of the septum primum grows caudally toward the

3. The ostium primum, a foramen, is diminishing.

Note: The fetal heart chambers and outflow tracts contain foramenina and ducts that shunt the
oxygenated blood entering the right atrium to the left ventricle and aortic arch, thus largely bypassing
the pulmonary circulation. These shunts close at birth, abruptly separating the two circulation systems
(example: Ductus Arteriosus!a connection between the pulmonary artery and aorta. When it closes it
forms the ligamentum arteriosum. A Patent Ductus Arteriosus occurs when this shunt does not close. It
is very common in premature infants and maternal rubella infection. Prostaglandin synthesis inhibitors
can be used to promote closure).

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B. Septum primum and septum intermedium fusion.

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1. The left, right, superior, and inferior endocardial cushions begin to form around the periphery of the
atrioventricular canal.
2. Late 6th week, the superior and inferior cushions meet and fuse, forming the septum intermedium.
This divides the common atrioventricular canal into right and left atrioventricular canals (Fig 7-15A, 7-16,
and 7-17C).
3. End of the 6th week, the growing edge of the septum primum fuses with the septum intermedium
(Fig 7-15A and Fig 7-19D).

4. Fusion destroys the ostium primum. Programmed cell death near the superior edge of the septum
primum creates a hole, forming a new foramen, the ostium secundum. Thus, a new channel for right-toleft shunting opens before the old one closes.

C. An incomplete septum secundum forms next to the septum primum.

1. A second crescent shaped ridge of tissue (the septum secundum) appears on the ceiling of the right
atrium adjacent to the septum primum (Fig 7-15).

2. The foramen ovale is formed near the floor of the right atrium (Fig 7-16).

3. Throughout fetal life, blood shunts from the right atrium to the left atrium passing through the
foramen ovale and ostium (foramen) secundum.

Note: Dilation of pulmonary vasculature and cessation of umbilical flow reverses the pressure
difference, pushing the flexible septum primum against the more rigid septum secundium. This closes
the shunt a birth.

V. Realignment of the heart (Fig 7-17).

A. The atrioventricular canal is repositioned to the right.


1. During the 5th week, the right side of the canal comes into alignment with the future right atrium
and right ventricle.

2. At the same time, the canal is being divided into right and left canals by the growth of the superior
and inferior endocardial cushions.

3. The new alignment simultaneously provides the left ventricle with a direct outflow path through the
conus cordis to the truncus arteriosus.

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VI. Formation of the atrioventricular valves and septation of the ventricles and outflow tracts.

A. Septation of the ventricles (Fig 7-18 & 7-19).

1. End of the 4th week, the muscular ventricular septum begins to grow towards the septum
intermedium, but halts in the middle of the 7th week before they touch.

Note: If fusion occurred to soon, the left ventricle would be shut off from the ventricular outflow tract.

2. Myocardium begins to thicken and myocardial ridges or trabeculae appear on the inner wall of both
ventricles.

3. On the right wall of the muscular ventricular septum the moderator band (prominent trabeculation)
has formed. This region connects the muscular septum with the anterior papillary muscle (forms part of
the right atrioventricular valve) (Fig 7-18B & Fig 7-19).

B. Atrioventricular valve formation (Fig 7-19).


1. 5th-8th weeks, atrioventricular valves form.

2. Anterior and posterior cusps (leaflets) form on either side of the both canals (Fig
7-19D).

3. The free edge of each leaflet is attached to the venticular walls by the chordae tendinae which insert
into the papillary muscles of the myocardium (Fig19C,D).

Note: The valve leaflets are designed so that they fold back to allow blood to enter the ventricles from
the atria during diastole but shut to prevent backflow when the ventricles contract (systole).

4. During the third month the right atrioventricular valve (tricuspid valve) usually develops a third small
septal cusp. The left atrioventricular valve (bicuspid valve) has only anterior and posterior leaflets (Fig 719D).

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C. Septation of the cardiac outflow tract and final septation of the ventricles (Fig 7-20).

Note: Further septation of the ventricles and the outflow tract must occur in tight coordination to
produce a functional heart. A large proportion of cardiac defects are due to errors during the septation
process.

1. Beginning of the 5th week, the right and left truncoconal swellings (truncoconal septae) grow out
from the walls of the common ventricular outflow tract at the junction of the truncus arteriosus and
conus cordis (Fig 7-20A,B).

2. When they meet , they begin to fuse together superiorly and inferiorly ( the growing membranous
ventricular septum), separating the right (eventually the pulmonary trunk) and left (eventually the
ascending aorta) ventricular outflow pathways. Septation is complete when the truncoconal swellings
fuse with the inferior endocardial cushion and the muscular interventricular septum, thus separating the
right and left ventricles.

Note: Failure of complete fusion, resulting in a ventricular septal defect


(membranous), is the most common congenital heart defect.

3. The growing truncoconal septae apparently arise in a spiral along the walls of the truncus arteriosus
and the ventricular outflow tracts. As a result, the left and right ventricular outflow tracts (eventually
the aorta and pulmonary trunk) twist around each other in a helical arrangement (Fig 7-20).

4. Truncus swelling also contribute to the semilunar valves in the aortic and pulmonary trunks via the
initial formation and splitting of tubercles (Fig 7-21). The tubercles give rise to the cusps of the threecusped semilunar valves that prevent backflow from the aorta and pulmonary trunk into the ventricles.

D. Neural crest contribution to the truncoconal septum (Fig 7-29).

1. The critical components of the truncoconal septum are derived from the cardiac neural crest.

2. Cardiac neural crest invade the truncoconal swellings after migrating through the pharyngeal arches
3, 4, and 6.

3. Cardiac neural crest cells give rise to:


a. connective and smooth muscle of the truncoconal septa. b. Cardiac ganglia

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4. Cardiac neural crest ablation revealed the role of neural crest in normal and aberrant septation of the
cardiac outflow tracts. If the cardiac neural crest is removed before it begins to migrate, the
truncoconal septa completely fail to develop, and blood leaves both ventricles through a persistent
truncus arteriosus.

5. Other anomalies after cardiac neural crest ablation include:

a. dextroposed aorta

b. ventricular septal defects

c. tetralogy of Fallot

6. Also the pathways that cardiac neural crest cells migrate through are very important. For example,
the CHARGE and DiGeorge syndromes (which have cardiac anomalies) result from defects of the
pharyngeal arches.

VII.

Clinical applications of Congenital Cardiovascular Disease.

A. Stats on cardiovascular malformations.

1. Cardiovascular malformations are the most common type of life-threatening congenital defect.

2. Congenital cardiovascular malformations account for about 20% of all congenital defects observed in
live-born infants (8 of every 1,000 live births).

3. Ventricular septal defects (membranous) are the most common congenital cardiovascular
malformation.

B. Cause of cardiovascular malformations.

1. Neither the cause nor the pathogenesis of most heart defects is understood. A few can be associated
with specific genetic errors or environmental teratogens, but the etiology of most malformations appear
to be multifactorial.

2. Single-gene mutations causing cardiac malformations:

a. Familial hypertrophic cardiomyopathy (FHC): gradual thickening of the ventricular walls and
interventricular septum, disorganization of the muscle fibrils, and formation of loose connective tissue.
These defects can cause arrhythmias and pumping inefficiency, leading to cardiac failure and sudden
death in early adulthood. (mutation of the beta-cardiac myosin heavy chain gene)

b. Congenital long QT syndrome: causes cardiac arrhythmias (repolarization of the ventricle--resting


EKG is abnormal), leading to fainting and sudden death (mutation in one of the cardiac ion channels).

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3. Perturbation of any normal process of heart development may result in malformation.

a. Acardia (Fig 7-22): Error in primitive heart tube formation.

b. Dextrocardia (Fig 7-23): The primative heart tube folds to the right instead of to the left. Most
individuals with Dextrocardia exhibit situs inversus.

c. Atrial Septal (Septum Secundum) Defect (Fig 7-24): The septum secundum is too short to cover the
ostium secundum completely. Thus when the septum primum and septum secundum are pressed
together at birth the atrial septae persists, causing a continued mixing of right and left atrial blood after
birth. Infants with this abnormality are generally asymptomatic, but the persistent increase in flow to
the right atrium may lead to the enlargement of the right ventricle and pulmonary trunk. Cardiac failure
may ensue later in
life. This is a common malformation of trisomy 21.

d. Atrioventricular Septal Defect (endocardial cushion defect): Arises from failure of the superior and
inferior endocardial cushions to fuse. Most common cardiac malformation in Down Syndrome. It
results in persistent left-to-right shunting of blood after birth. In severe cases congestive heart failure
may occur.

e. Double-outlet left ventricle malformation: The aortic and pulmonary outflow tracts both connect to
the left ventricle. The right ventricle becomes hypoplastic because it has no outflow tract.

f. Ventricular Septal Defects: The most common of all congenital heart malformations. This defect can
arise from several causes. One example, is the failure of the muscular and membranous ventricular
septa to fuse. Membranous is the most common type.

g. Tricuspid and mitral valve defects: Valve Atresia is the complete loss of the valve orifice. Ebsteins
disease (tricuspid valve anomaly) causes a displaced valve and abnormal shaped leaflets. The
dysfunctional valve allows blood to regurgitate into the right atrium and also blocks access to the
pulmonary trunk. This causes cyanosis (in adequate oxygenated blood) and an enlarged left ventricle in
the newborn.

h. Persistent Truncus Arteriosus (Fig 7-26A): because of abnormal neural crest the truncoconal septa do
not form at all, resulting in blood that mixes from both sides of the heart in the common outflow tract
(ventricular septal defect also occurs). Thus both the body and the lungs receive partially deoxygenated

blood. Untreated infants usually die within the first 2 years. Surgical correction is very difficult (75%
mortality).

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i. Transposition of the great vessels (Fig 7-26B,C): The truncoconal septa develop but do not display the
usual spiral pattern. This results in a left ventricle that empties into the pulmonary circulation and a
right ventricle that empties into the systemic circulation. This defect is the leading cause of death in
infants under 1 year old with cyanotic heart disease. Why is this condition not immediately fatal?

j. Tetralogy of Fallot (Fig 7-27): Represents a group of cardiac malformations that arise through a
pathogenetic cascade (a primary malformation sets off a cascade of effects that lead to other
malformations). The four classic malformations in this syndrome are pulmonary stenosis, ventricular
septal defect, overriding aorta, and right ventricular hypertrophy. The primary defect is a malalignment
of the muscular outlet septum between the subpulmonary and subaortic outlets.

k. Hypoplastic left heart: Occurs when the normal shunting of blood from the right to the left atrium
during gestation is restricted. The left side of the heart becomes underdeveloped. This syndrome has a
multifactorial etiology, but it can be associated with the genetic disease phenylketonuria.

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Gastrointestinal Tract Development


Body Cavities / Foregut

I. Embryonic folding of the trilaminar germ disc.

A. Foregut, midgut, and hindgut formation.

1. The foregut, midgut, and hindgut of the primitive gut tube are formed by the combined action of
differential growth and lateral and cephalocaudal folding (during the 3rd and 4th weeks) (Fig 3-6 , Fig 41, Fig 6-1, Fig 9-1, Fig 9-10).

2. As folding occurs, the embryo grows faster than the yolk sac, converting the flat trilaminar germ disc
into an elongated cylinder.

3. The cylinder consists of three concentric nested tubes: Ectoderm (outer layer), Endoderm (central
layer, primary gut tube), and Mesoderm (separates ectoderm and endoderm and contains the coelom)
(Fig 6-1& Fig 4-1). Thus, the three germ layers retain the same topological relation to each other.

4. Fusion of the ectoderm, mesoderm, and endoderm from opposite sides is prevented in the
immediate vicinity of the vitelline duct but not in more cranial and caudal regions.

B. Arterial supply distinguishes the foregut, midgut, and hindgut.

1. The gut tube initially consists of cranial and caudal blind-ending tubes, the presumptive foregut
(terminates in the buccopharyngeal membrane) and hindgut, (terminates in the cloacal membrane) and
a central midgut, which still opens ventrally to the yolk sac (Fig 9-1).

2. The neck of the yolk sac narrows and becomes the vitelline duct. The vitelline duct and yolk sac are
eventually incorporated in the umbilical cord.

3. The gut tube and its derivatives are vascularized by the unpaired ventral branches of the descending
aorta (Fig 8-5).

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4. Fourth week, vitelline arteries emerge from the ventral surfaces of the dorsal aortae to supply the
yolk sac. By the end of the fourth week many of the vitelline channels disappear, leaving five in the
thoracic region (supplies the thoracic part of the foregut--the pharynx and thoracic esophagus) and
three (the celiac, superior mesenteric, and inferior mesenteric arteries) in the abdominal region (Fig 85).

5. Celiac trunk artery: supplies the abdominal foregut--the abdominal esophagus, stomach, and
superior half of the duodenum and its derivatives.

6. Superior mesenteric trunk artery: supplies the midgut.

7. Inferior mesenteric artery: supplies the hindgut.

C. The primitive abdominal gut is suspended by the dorsal mesentery.

1. By the end of the fourth week, the portion of the gut tube within the peritoneal cavity (the
abdominal esophagus to the superior end of the developing cloaca) hangs suspended by the dorsal
mesentery (Fig 9-2).

2. In the stomach region the gut tube remains connected to the ventral body wall by the thick septum
transversum. By the fifth week, the caudal portion of the septum transversum thins to form the ventral
mesentery (connects stomach and liver to the ventral body wall) (Fig 9-2).

3. Septum transversum: on day 22 it appears as a thickened bar of mesoderm lying between the
cardiogenic area and the cranial margin of the embryonic disc (Fig 6-1, Fig 6-5, & 9-2). Cephalic folding
wedges the mesoderm between the cardiogenic region and the neck of the yolk sac (Fig 6-1). Thus, it
forms a ventral partition separating the intraembryonic coelomic cavity into a primitive pericardial cavity
superiorly and a peritoneal cavity inferiorly (Fig 6-5). These two cavities remain in continuity through
the posterior pericardioperitoneal canals. The septum transversum eventually gives rise to part of the
diaphragm and the ventral mesentery of the stomach and duodunum.
4. Early 5th week to the 7th week, a pair of transverse membranes, the pleuroperitoneal membranes
(gives rise to the posterior region of the diaphragm) grow from the posterior body wall to meet the
posterior edge of the septum transversum. This closes the pericardioperitoneal canals (Fig 6-7 A,B).

Note: The left pericardioperitoneal canal is larger than the right and closes later. This difference may
account for the fact that congenital diaphragmatic hernias of the abdominal viscera are more common
on the left side than on the right.

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II. The abdominal foregut development.

A. The abdominal foregut gives rise to the stomach, duodenum, liver, pancreas, and gall bladder.

B. The stomach rotates as it develops.


1. Early 4th week, the stomach becomes apparent as the foregut inferior to the septum transversum
expands slightly (Fig 9-3). The thoracic foregut also begins to elongate (days 26-28).
2. 5th week, the dorsal wall of the stomach grows faster than the ventral wall, forming the greater
curvature of the stomach and the lesser curvature of the stomach.
3. 7th week, the fundus and cardiac incisure results from the continued differential expansion of the
superior part of the greater curvature.
4. 7th and 8th weeks, the stomach (and the dorsal/ventral mesentery & the left/right vagal branches)
rotates 90 degrees around the craniocaudal axis so that the greater curvature lies to the left and the
lesser curvature lies to the right (Fig 9-3D). The stomach also rotates slightly around a ventrodorsal axis
so
that the greater curvature faces slightly caudally and the lesser curvature slightly cranially.

5. The differential thinning of the right side of the dorsal mesogastrium (the portion of the dorsal
mesentery attached to the stomach) is also believed to play a role in the rotation process.

C. Formation of the lesser/ greater sac and the greater omentum of the peritoneal cavity (Fig 9-5).

1. When the duodenum swings to the right, it fuses to the dorsal body wall, enclosing the space (the
lesser sac) posterior to the stomach and within the expanding cavity of the greater omentum . The rest
of the peritoneal cavity is called the greater sac. The principal passageway between the greater and
lesser sacs is the epiploic foramen of Winslow. It is the repositioning of the stomach, liver, and lesser
omentum (mentioned later) that forms this narrow canal.

2. The rotation of the stomach and growth of the dorsal mesogastrium creates the greater omentum
that dangles from the greater curvature of the stomach (drapes over more inferior organs of the
abdominal cavity).

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3. The upper recess of the lesser sac is the portion of the lesser sac directly dorsal to the stomach. The
cavity within the greater omentum is called the lower recess of the lesser sac. Eventually, during fetal
life, the anterior and posterior folds of the greater omentum fuse together obliterating the lower recess.

D. Endodermal buds of the duodenum give rise to the digestive glands (Fig 9-6).

1. Day 22, the hepatic plate, a small endodermal thickening, appears on the ventral side of the
duodenum.

2. The next few days, the hepatic plate proliferates and forms the hepatic diverticulum (gives rise to the
ramifying liver cords (hepatocytes) to the bile canaliculi and hepatic ducts), which grows into the inferior
region of the septum transversum.

3. The mesoblastic supporting stroma of the liver develops from splanchnopleuric mesoderm
originating near the cardiac region of the stomach.

4. The liver is a major early hematopoietic organ of the embryo.

5. Day 26, the cystic diverticulum (gives rise to the gallbladder and cystic duct) forms first as a
endodermal thickening on the ventral side of the duodenum at the base of the hepatic diverticulum. It
eventually buds into the ventral mesentery.

6. The common bile duct forms at the junction of the hepatic and cystic ducts.

Note: The gallbladder and cystic duct develop from histologically distinct populations of duodenal cells.

7. Also on day 26, the dorsal pancreatic bud (eventually gives rise to the head, body, and tail of the
pancreas) forms opposite of the hepatic diverticulum and grows into the dorsal mesentery. As it
elongates, the ventral pancreatic bud (eventually connected to the common bile duct and gives rise to
the uncinate process) sprouts into the ventral mesentery just caudal to the developing gallbladder.
8. 5th week, the mouth of the common bile duct and the ventral pancreatic bud migrate posteriorly
around the duodenum to the dorsal mesentery.

Note: An annular pancreas is a condition that arises because the two lobes of the ventral (a normal
variation) pancreatic bud migrate in opposite directions around the duodenum to fuse with the dorsal
pancreatic bud. This compresses the duodenum and may cause gastrointestinal obstruction (Fig 9-7).

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9. Late 6th week, the two pancreatic buds fuse to form the definitive pancreas which fuses to the dorsal
body wall like the duodenum. The duct from the dorsal bud to the duodenum usually degenerates (can
persist as an accessory pancreatic duct draining into the minor duodenal papilla), leaving the ventral
pancreatic duct (main pancreatic duct) as the only conduit to the duodenum.

10. The main pancreatic duct and the common bile duct meet and empty into the duodenum at the
major duodenal papilla (ampulla of Vater).

III. Spleen development (a vascular lymphatic organ).

A. Spleen is derived from the dorsal mesogastrium, not from the gut tube endoderm.
1. Late 4th week, a mesenchymal condensation develops in the dorsal mesogastrium of the lesser sac.
2. 5th week, the condensation differentiates into the spleen. Accessory spleens
may also develop near the primary spleen.

3. The rotation of the stomach and growth of the dorsal mesogastrium translocate the spleen to the left
side of the abdominal cavity. Also, the rotation of the dorsal mesogastrium forms the renal splenic
ligament between the spleen and the left kidney. The portion of the dorsal mesentery between the
spleen and the
stomach is the gastroplenic ligament.

B. Functions of the spleen.

1. Until the 14 week, the spleen is strictly hematopoietic.

2. 15 to 18 weeks, the transformation stage, the organ develops a lobular architecture. After this stage,
the stage of lymphoid colonization begins as T- lymphocyte precursor cells begin to enter the spleen.

3. 23 weeks, B-cell precursors arrive and form the B-cell regions of the definitive spleen. At this point
the spleen has acquired its definitive lymphoid character.

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IV. Formation of the liver and associated membranes.

A. Growing liver bud and developing serosal membranes.

1. As the liver bud (an outgrowth from the ventral surface of the foregut) grows into the ventral
mesentery (caudal region of the septum transversum), its crown moves toward the developing
diaphragm. Eventually, this region of the septum transversum will give rise to a number of membranous
structures, including the serous (derived from splanchnic mesoderm) coverings of the liver and the
membranes that attach the liver to the stomach and to the ventral body wall (Table 9-2).
2. 6th week, The enlarging liver makes contact with the superior and inferior coverings of the septum
and begins to split them apart (Fig 9-8).

3. Inferior covering (serosal membrane) of the septum becomes the visceral peritoneum that covers
almost the entire surface of the liver.

4. The superior end of the liver makes direct contact with the developing central tendon of the
diaphragm (which had formed from the superior region of the septum transversum) and thus has no
peritoneal covering (bare area of the liver) (Fig 9-8).

B. Ligament formation.

1. The coronary ligament subsequently developes as a fold or reflection around the margin of the bare
area. In the bare area where the liver and diaphragm come in direct contact, the hepatic portal vessels
and the systemic veins of the diaphragm anastomose.

2. The membranous falciform ligament arises from the ventral mesentery that attaches the liver to the
ventral body wall. The free caudal margin of this membrane carries the umbilical vein from the body
wall to the liver.

3. The ventral mesentery between the liver and the stomach thins out to form a translucent membrane
called the lesser omentum.

4. The caudal border (of the lesser omentum) connecting the liver to the duodenum is called the
hepatoduodenal ligament (contains the portal vein, hepatic arteries, hepatic duct, cystic duct, and
common bile duct).

5. The region of the lesser omentum between the liver and the stomach is called
the hepatogastric ligament.

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Gastrointestinal Tract Development


Midgut / Hindgut

V. Rotations of the midgut and subsequent reconfiguration of the small and large intestine.

A. Ileum elongation.
1. 5th week, the presumptive ileum (the cecal primordium is at the junction between the ileum and the
colon) begins to elongate rapidly.

2. The ileum grows more rapidly than the abdominal cavity, causing the midgut to form a dorsoventral
hairpin called the primary intestinal loop (Fig 9-9A).

3. The cranial limb of the loop will give rise to most of the ileum.

4. The caudal limb of the loop will give rise to the ascending and transverse colons.

5. The apex of the primary intestinal loop is attached to the umbilicus by the
vitelline duct.

6. The superior mesenteric artery runs down the long axis of the loop.
7. Early 6th week, due to pressure from the growing liver and elongating midgut the primary intestinal
loop herniates into the umbilicus (Fig 9-9B).

B. 90-degree counterclockwise rotation of the primary intestinal loop.

1. During the herniation process the primary intestinal loop rotates around the axis of the superior
mesenteric artery (dorsoventral axis).

2. As viewed from the front, it rotates 90-degrees counterclockwise. Thus, the cranial limb moves
caudally and to the embryos right, while the caudal limb moves cranially and to the embryos left (Fig 99B).

3. 8th week, the first rotation is complete. At the same time the lengthening jejunum and ileum
(midgut) develop into a series of folds called the jejunal-ileal loops. The expanding cecum sprouts a
vermiform appendix (wormlike) (Fig 99C).

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C. Retraction and additional rotation of the midgut.

1. The retraction of the midgut into the abdominal cavity is poorly understood.

2. As the intestinal loop re-enters the abdomen it rotates an additional 180 degrees counterclockwise.
Thus the retracting colon has rotated a total of
270 degrees relative to the posterior wall of the abdominal cavity (Fig 9-9C-E).

3. 11th week, rotation and retraction are complete. The cecum is now in a position just inferior to the
liver. Between the 73rd and 77th days, the cecum is displaced inferiorly, pulling down the proximal
hindgut to form the ascending colon (midgut).

D. The mesenteries shorten and fold, reconfiguring the midgut (Fig 9-10).

1. The dorsal mesenteries of the ascending colon and descending colon shorten and fold. This bings the
these organs into contact with the dorsal body wall, where they adhere and become secondarily
retroperitoneal.

a. Intraperitoneal viscera! the abdominal gut tube and its derivatives that are suspended (from dorsal
mesentery) in what will later become the peritoneal cavity (Fig 6-4).

b. Retroperitoneal viscera! organs that are not suspended by mesentery. It means that an organ is
located behind the peritoneum from a viewpoint inside the peritoneal cavity. Thus the kidneys and
bladder are an example of retroperitoneal (Fig 6-4).

c. Secondarily retroperitoneal! some parts of the gut tube that are initially suspended by mesentery
later become fused to the body wall, thus taking on the appearance of retroperitoneal organs.
Examples of secondarily retroperitoneal are the ascending and descending colon, the duodenum, and
the pancreas (Fig 6-4).

2. The transverse colon does not become fixed to the body wall but remains an intraperitoneal organ
suspended by mesentery.

3. The sigmoid colon (the most inferior portion of the colon) also remains suspended by mesentery.

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VI. The distal hindgut gives rise to the rectum and the urogenital sinus (Fig 9-11).

A. Partition of the cloaca.

1. The part of the primitive gut tube lying beneath the cloacal membrane forms an expansion called the
cloaca.
2. 4th-6th weeks, the cloaca is partitioned into a posterior rectum and an anterior primitive urogenital
sinus (gives rise to the bladder, the pelvic urethra, and urogenital sinus) by the growth of the coronal
partition called the urorectal septum (Fig 9-11).

3. The distal edge of the urorectal septum fuses with the cloacal membrane.
This divides the membrane into an anterior urogenital membrane and a
posterior anal membrane.

4. The zone of fusion between the urorectal septum and the cloacal membrane becomes the perineum.

B. The two intergrated mesodermal septal systems of the urorectal septum.

1. Recent evidence suggests that the urorectal septum is formed by the intergration of the Tourneux
fold and a pair of lateral folds called the Rathke folds (Fig 911).
2. 4th week, the Tourneux fold, a crescentic wedge of mesoderm, grows inferiorly between the allantois
and the cranial end of the cloaca. It ceases to grow when it reaches the level of the future pelvic urethra.
The Rathke folds (mesoderm) arise from either side of the cloacal cavity and grow toward the midline.
The Rathke folds then fuse with each other and the Tourneux fold to complete the urorectal septum (Fig
9-11).

C. Anorectal canal formation (Fig 9-12).

1. The superior two-thirds of the anorectal canal forms from the distal part of the hindgut.

2. The inferior one-third of the anorectal canal is derived from an ectodermal pit
(anal pit or proctodeum).

3. In the adult, the border between the superior end of the anal pit and the inferior end of the rectum is
demarcated by the mucosal folds (pectinate line).

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4. The vasculature of the anorectal canal is consistent with this dual origin.

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Branches of the inferior mesenteric arteries and veins that serve the hindgut also supply the region
superior to the pectinate line. The region inferior to the pectinate line, however, is supplied by the
branches of the internal iliac arteries and veins.

Note: The tributaries of the superior rectal vein and the tributaries of the inferior rectal vein
anastomose within the mucosa of the anorectal canal. If the blood flow into the inferior vena cava is
blocked it may cause this region to swell into hemorrhoids.

D. Digestive tube recanalization.


1. 6th week, the endodermal epithelium of the gut tube proliferates until it completely ocludes the gut
tube lumen (Fig 9-13).
2. 7th & 8th weeks, the gut tube is recanalized by the formation of vacuoles that eventually coalesce.
3. 9th week, the endodermal lining of the new gut differentiates into the definitive mucosal epithelium.

Note: Stenosis or duplication of the digestive tract may result from incomplete recanalization (Fig 9-13).

VII.

Clinical applicationsanomalies of gastrointestinal development.

A. Anterior abdominal wall defects.

1. Omphalocele! organs protrude from the anterior abdominal wall due to the failure of the umbilicus
to close completely (2.5 of 10,000 births).

a. In some individuals, the herniation of the midgut in the 6th week occurs normally, but the organs do
not retract properly in the 10th week (organs protrude into a thin/ruptured amniotic membrane only)
(Fig 9-14A).

b. In other individuals, the organs retract properly, but then herniate secondarily because the ventral
abdominal wall fails to close in the region of the umbilicus (organs protrude into a sac composed of
peritoneum, subserous fascia, and amniotic membrane).

2. Ectopia cordis! The abdominal wall defect in an omphalocele is not always limited to the umbilicus.
In this case there is a defect of the abdominal wall cranial to the umbilicus, causing the heart to
eventrate (Fig 9-14B).

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3. Pentalogy of Cantrell! sometimes a omphalocele may occur in conjunction with a variety of cardiac
and renal defects. In this case an omphalocele, diaphragmatic hernia (Which side would this most likely
occur?), sternal cleft, ectopia cordis, and intracardiac anomaly.

4. Gastroschisis! a defect of the ventral abdominal wall between the developing rectus muscles just
lateral to the umbilicus (does not involve the umbilicusit closes normally) (Fig 9-15). This defect
usually occurs on the right side due to an abnormal involution of the right umbilical vein and the
consequent maldevelopment of the ventral abdomianl wall in that region. Organs rarely eventrate, but
if they do they are not enclosed in an amnioperitoneal sac. This disorder is also less likely to be
associated with other abnormalities (including chromosomal).

5. Epispadias! the left and right halves of the penile tubercle do not fuse completely. Early in the fifth
week, the cloacal folds (pair of swellings) develop on either side of the cloacal membrane and eventually
go on to form the genital tubercle (Fig 10-18) ). Thus, hindgut structures are exposed through the
defective penile urethra opening.

6. Exstrophy of the bladder! the bladder is revealed by an abdominal wall defect.

7. Exstrophy of the cloaca! both the bladder and the anorectal canal are exposed (Fig 9-16).

Note: #5-7 have abdominal wall defects (secondarily) due to the anomalous development of the cloacal
membrane (either enlarged cloacal membrane or precocious disruption of the cloacal membrane).
These malformations are about twice as common in males as in females.

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B. Abnormal rotation and fixation of the midgut.

1. Nonrotation of the midgut (left-sided colon)! arises when the primary intestinal loop fails to undergo
the normal 180-degree counterclockwise rotation as it is retracted into the abdominal cavity (Fig 9-17).
The cranial limb of the primary intestinal loop ends up on the right side, while the caudal limb of the
primary intestinal looop (presumptive colon) ends up on the left side. Also, the secondarily
retroperitoneal placement (fusion to dorsal body wall) of the intestine may not occur.

2. Reversed rotation of the midgut! the 180degree rotation occurs clockwise instead of
counterclockwise, so the net rotation of the midgut is 90 degree clockwise (Fig 9-18). The duodenum
lies ventral to the transverse colon instead of dorsal to it. The duodenum does not become secondarily
retroperitoneal, but the transverse colon does (it is normally intraperitoneal).

3. Mixed rotations of the midgut (malrotations)! mixed or uncoordinated behavior of the two limbs of
the primary intestinal loop. The cephalic limb of the primary intestinal loop undergoes only the initial
90-degree rotation, whereas the caudal limb undergoes only the later 180-degree rotation (Fig 9-19).
The duodenum becomes fixed on the right side of the abdominal cavity, and the cecum becomes fixed
near the midline (just inferiror to the pylorus of the stomach). The abnormal placement of the cecum
may cause the duodenum to be enclosed by a band of thickened peritoneum.

Note: A significant number of intestinal obstruction (or constriction) cases are caused by abnormal
rotation (or fixation) of the midgut. Specific regions of the intestine can be pinned against the dorsal
body wall by bands of abnormal mesentery. Also, the malrotation may cause the midgut to be
suspended from a single point of attachment on the dorsal body wall. These suspended coils are prone
to volvulus (bilious vomiting is a common symptom) (Fig 9-20). The intestinal volvulus may also
compress part of the intestinal vasculature (leads to intestinal ischemia or infarction) or lymphatic
vessels (leads to venous mucosal engorgement and consequent gastrointestinal bleeding).

The presence of a rotational abnormality is usually signaled during childhood by abdominal pain,
vomiting, gastrointestinal bleeding, or failure to thrive (some case are silent until adulthood). These
defects can be repaired surgically.

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C. Vitelline duct and allantois defects.

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1. Meckels diverticulum! the vitelline duct normally regresses between the 5th and 8th weeks, but in
this disorder it persists as a remnant of variable length and location (Fig 9-21). Meckels diverticulum
can manifest any of the followin conditions:

a. Typical Meckels diverticulum! a fingerlike projection of the ileum located about 100cm proximal to
the cecum.

b. Omphalomesenteric fistula! a patent fistula connects the umbilicus with the ileum.

c. Omphalomesenteric cyst! an isolated cyst suspended by ligaments.

d. Omphalomesenteric ligament! a fibrous band connecting the ileum and anterior body wall at the
level of the umbilicus.

Note: Twice as common in males. Individuals with a Meckels diverticulum develop symptoms of
intestinal obstruction, gastrointestinal bleeding, or bowel sepsis. Symptoms may closely mimic
appendicitis.

2. Urachal anomalies! caused by the incomplete obliteration of the lumen of the allantois and bladder
apex. The urachus or median umbilical ligament is formed from the allantois and constricted bladder
apex. This band runs from the bladder to the umbilicus (Fig 9-22A). In very rare cases the allantois or

bladder apex remain patent, resulting in a patent urachus, umbilical urachal sinus, vesicourachal
diverticulum, or urachal cyst (Fig 9-22B-E).

Note: The initial symptoms of infection (due to leakage of urine from the umbilicus, urinary tract
infections, and peritonitis) are easily confused with those of appendicitis.

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Urogenital System Development


Renal System Development

I. Development of Three Nephric Systems.

Note: The intermediate mesoderm (Fig 10-1) gives rise to the nephric structures
of the embryo, to portions of the gonads, and to the male genital duct system. Three sets of nephric
structures (cervical nephrotomes, mesonephroi, and

metanephroi, the definitive kidneys) develop in craniocaudal succession from the intermediate
mesoderm.

A. Cervical nephrotomes.
1. Early 4th week! five to seven paired cervical segments of intermediate mesoderm give rise to a
nephric vesicle/nephrotome (small, hollow ball of epithelium) (Fig 10-2A).

2. Also referred to as the pronephros (Greek for first kidney) because they resemble the functional
embryonic pronephroi of some lower vertebrates.

3. The cervical nephrotomes are transient and nonfunctional. They disappear by day 24 or 25.

B. Mesonephroi.
1. Early 4th week! nephric (mesonephric) tubules develop within a pair of mesonephroi/mesonephric
ridges (elongated swellings of intermediate mesoderm located on either side of the vertebral column)
from the upper thoracic region to the third lumbar level (Fig 10-2B-D).
2. Also early in the 4th week! the mesonephric ducts (intermediate mesoderm origin) first appear in the
form of a pair of solid longitudinal rods (dorsolateral to the developing mesonephric tubules) (Fig 10-2A
& Fig 10-3). These rods grow caudally into the lower lumbar region guided by an adhesion gradient
between the ectoderm and endoderm.

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3. By day 26, the rods diverge from the intermediate mesoderm and fuse with the ventrolateral walls of
the cloaca (Fig 10-2 & Fig 10-4). The region of fusion eventually becomes the posterior wall of the future
bladder. During the fusion process the rods also begin to cavitate at their distal ends, forming a lumen.
Cavitation progresses cranially forming the mesonephric ducts.
4. End of 5th week! the cranial regions of the mesonephroi undergo regression, leaving about 20 pairs
of tubules occupying the first three lumbar levels.

5. The mesonephric tubules differentiate into excretory units that resemble an abbreviated version of
the adult nephron (Fig 10-2D).

6. The medial end of the tubule forms the Bowmans capsule (a cup-shaped sac) which raps around the
glomerulus (a knot of capillaries produced on branches of arteries sprouting from the dorsal aorta),
forming the renal corpuscle.

7. Each renal corpuscle and nephric tubule is called a mesonephric excretory unit.

8. The lateral tip of each mesonephric tubule fuses with the mesonephric duct, opening a passage from
the excretory units to the cloaca.
9. 6th to 10th weeks! the mesonephric excretory units are functional and produce small amounts of
urine.

10. After 10 weeks! the mesonephric excretory units cease to function and then regress. The
mesenephric ducts regress in the female, but in the male the mesonephric ducts plus a few modified
mesonephric tubules persist and form parts of the male genital duct system (we will talk about in more
detail in the next lecture).

C. Metanephroi or the definitive kidneys.


1. 4th week (day 28)! the distal portion of the mesonephric ducts sprout ureteric buds (eventually
differentiates into the ureters and the collecting duct system of the kidneys) which induce the
metanephroi to form in the intermediate mesoderm of the sacral region (Fig 10-4A).

2. Day 32! each ureteric bud penetrates the metanephric blastema (a portion of the sacral intermediate
mesoderm which appears around the same time) and begins to bifurcate (Fig 10-4B). The metanephros
become lobulated in appearance as each ampulla (growing tip of each bifurcated branch) acquires a
caplike aggregate of metanephric blastema tissue. The metanephric blastema eventually differentiate
into the nephrons (the definitive urine-forming units of the kidneys).
3. Middle of 6th week! the developing metanephros consists of two lobes separated by a sulcus (Fig 104C).

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4. By the end of the 16th week! the metanephros consists of 14 to 16 lobes (Fig
10-4D) and the sulci between the lobes begin to fill in.

Note: The ureteric bud and metanephric blastema exert reciprocal inductive effects (classic model of
induction). Several hours of direct contact with a ureteric bud ampulla are required to induce nephron
differentiation in blastema tissue and the reciprocal inductive signals from the metanephric blastema
regulate the orderly bifurcation of the tips of the ureteric buds (discussed in more detail below). If the
ureteric bud is abnormal or missing, the kidney does not develop.

II. Collecting duct system (entirely the product of the ureteric bud) of the
Metanephroi.

Note: The collecting duct system is produced by sequential bifurcation of the ureteric bud. Urine
produced by the nephrons flows through the collecting tubules, minor calyces, major calyces, the renal
pelvis , and finally, the ureter. This path is called the collecting duct system.

A. Sequence of bifurcations (Fig 10-5 & Fig 10-6A).


1. Middle of the 4th week! when the ureteric bud first contacts the metanephric blastema, its tip
expands to form an initial ampulla that will give rise to the renal pelvis.
2. 6th week! the ureteric bud bifurcates four times, yielding 16 branches which coalesce to form two to
four major calyces extending from the renal pelvis.

3. 7th week! the next four generations of branches also coalesce to form the
minor calyces.

4. By 32 weeks! 11 additional generations of bifurcation have formed 1 to 3 million branches. These


will become the future collecting tubules (collecting ducts) of the kidney (Fig 10-6A).

B. Nephron development (Fig 10-6B-F).

1. Each nephron originates as a vesicle within the blastemic cap (surrounding the ampulla of a collecting
duct) (Fig 10-6B). The vesicle elongates into a tubule. And a capillary glomerulus forms near one end of
it.

2. The tubule epithelium near the differentiating glomerulus thins and then invaginates to form a
Bowmans capsule (surrounds the glomerulus).

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3. Just as in the mesonephros, the renal corpuscle consists of a Bowmans capsule and the glomerulus.

4. As the renal corpuscle is developing, the lengthening nephric tubule differentiates into the proximal
convoluted tubule, the descending and ascending limbs of the loop of Henle, and the distal convoluted
tubule.

5. The definitive nephron with its renal corpuscle is called a metanephric excretory unit.
6. By the 10th week! the tips of the distal convoluted tubules connect to the collecting ducts. The
metanephroi become functional. Blood plasma from the glomerular capillaries is filtered by the renal
corpuscle to produce a dilute glomerular filtrate. The filtrate is concentrated and converted to urine by
the convoluted tubules and the loop of Henle. The urine then passes down the collecting system into
the ureters and then the bladder.

Note: The main function of the fetal kidneys is not to clear waste (mainly handled by the placenta), but
instead it supplements the production of amniotic fluid. Thus fetuses with bilateral renal agenesis do
not make enough amniotic fluid (oligohydramnios), confining the fetus to an abnormally small amniotic
space.

C. Definitive kidney architecture (Fig 10-7).


1. 5th to 15th weeks! the definitive kidney architecture is created.

2. The kidney is divided into an inner medulla (contains the collecting ducts and the loops of Henle) and
an outer cortex (contains the nephrons).

3. Each minor calyx drains a tree of collecting ducts within the renal pyramid that converge to form the
renal papilla.

4. The renal pyramids of the kidney are separated by renal column/columns of Bertin (cortical tissue
that contains nephrons). Thus the cortical tissue covers the outside of the kidney, as well as projecting
towards the pelvis.

5. The nephrons arise from the cortical regions of the primary lobes of the metanephric blastema.

Note: Neural Crest contribute to the function of the Kidney. Neural crest cells invade the metanephroi
early in their development. The neural crest give rise to the neurons of the kidney that regulate blood
flow and secretory function. These neurons are located at the tips of the metanephric tissue caps during
nephron induction. Thus these neurons also play a role in the induction of nephron formation.

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III. Kidneys ascend from a sacral to lumbar location.

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A. Movement of the Kidneys.


1. 6th to 9th weeks! the kidneys ascend to a lumbar site just below the suprarenal glands. They follow
a path on either side of the dorsal aorta (Fig 10-8).

2. The mechanism responsible for the relocation of the kidneys is poorly understood. The differential
growth of the lumbar and sacral regions of the embryo may play a role.

3. The ascending Kidney is progressively revascularized by a series of arterial sprouts from the dorsal
aorta, and the original renal artery in the sacral region disappears (Fig 8-6).

Note: The right kidney usually does not rise as high as the left kidney because of the liver on the right
side.

B. Anomalies can arise during the ascent of the kidneys.

1. Some of the transient inferior renal arteries occasionally fail to regress. This results in the presence
of accessory renal arteries.

2. Also, rarely, a kidney completely fails to ascend, remaining as a pelvic kidney


(Fig 10-8C).

3. A U-shaped horseshoe kidney (crosses over the ventral side of the aorta) may also arise if the inferior
poles of the two metanephroi fuse during the ascent. This causes the kidney to become caught under
the inferior mesenteric artery and subsequently it does not reach its normal site (Fig 10-8D).

IV. The remainder of the urinary tract develops form the hindgut endoderm.

A. Cloacal expansion and partition.

1. As mentioned last week, the cloacal expansion of the hindgut is partitioned by the urorectal septum
into an anterior primitive urogenital sinus and a posterior rectum (Fig 10-9).

2. The primitive urogenital sinus is continuous superiorly with the allantois (a hindgut diverticulum that
extends into the umbilicus) and is bounded inferiorly by the urogenital membrane.

3. The primitive urogential sinus consists of a superior presumtive bladder,


pelvic urethrea (the narrow neck), and an inferior definitive urogenital sinus.

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4. In males, the pelvic urethra becomes the membranous and prostatic urethra
and the definitive urogenital sinus becomes the penile urethra.

5. In females, the pelvic urethra becomes the membranous urethra, and the definitive urogenital sinus
becomes the vestibule of the vagina.

B. Exstrophy of the mesonephric ducts and ureteric buds (Fig 10-10).

1. Weeks 4 to 6! Via the process of exstropy, the distal portions of the mesonephric ducts and attached
ureteric ducts become incorporated into the posterior wall of the presumptive bladder (Fig 10-10).

2. Exstropy refers to the eversion of a hollow organ. During this process the mouths of the mesonephric
ducts flare, expand, flatten, and blend into the bladder wall.

3. This process brings the openings of the ureteric buds into the bladder wall, while the opening of the
mesonephric duct is carried inferiorly to the level of the pelvic urethra. The mesonephric ducts open
into the pelvic urethra just below the neck of the bladder.

4. The triangular region of exstrophied mesonephric duct, which was incorporated into the posterior
bladder wall, forms the trigone of the bladder. Endoderm from the surrounding bladder wall grows over
the trigone, but it remains visible in the adult as a smooth triangular region lying between the openings
of the ureters laterally and superiorly, and the opening of the pelvic urethra inferiorly.

5. 12th week! Splanchnopleuric mesoderm associated with the hindgut forms the smooth muscle of
the bladder wall.

V. Clinical applications of urinary tract development.

A. Ureteric bud or metanephros defects.

Note: 10% of all newborns have a developmental abnormality of the urinary tract (most do not cause
clinical problems). 45% of childhood renal failure result form defective development of the ureteric bud
or metanephros. Since there is a reciprocal induction between the ureteric buds and the metanephric
blastema, abnormalities in one often cause abnormalities in the other.

1. Partial duplication of the the ureter! If the ureteric bud prematurely bifurcates it results in a Y-shaped
bifid ureter (Fig 10-23). Although the two branches of the Y arise from the same ureteric bud, the
contractions of their muscular walls appear to be asynchronous. This may result in stagnate urine that
predisposes the individual to infections of the ureter.

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Could an individual remain asymptomatic and how could this occur?

2. Ectopic ureter (complete duplication)! complete duplicate ureters result from the growth of two
ureteric buds. In this condition a mesonephric duct sprouts two ureteric buds, which penetrate the
metanephric blastema indepently (Fig 10-24).

a. The more caudal bud induces the formation of the caudal pole. During exstrophy, the caudal bud
incorporates into the bladder wall normally (forms a normal orthotopic, ureter connected to the
bladder).

b. The more cranial bud induces formation of the cranial pole of the kidney.
During exstrophy, the cranial bud is carried inferiorly along with the descending mesonephric duct. It
may form its final connection with any derivative of the distal mesonephric duct, pelvic urethra, or
definitive urogenital sinus. Thus it forms an inferior ectopic ureter.

c. In males, the ectopic ureter may drain into the prostatic urethra, the ejaculaotry duct, the vas
deferens, or the siminal vesicle. Thus they always open superior to the sphincter urethra muscle and do
not result in incontinence (but still can result in painful urination or recurrent infections).

d. In females, ectopic ureters oftern connect to the vestibule, the vagina, or the uterus (rarely), forming
extrasphincteric outlets. This results in incontinence, but can be surgically corrected.

Note: The normal ureter drains the lower pole of the kidney and the ectopic ureter drains the upper
pole. The observation that the resulting two ureters cross each other (called the Weigert-Meyer rule)
helped to deduce the mechanism of mesonephric duct exstrophy.

B. Ureteric bud or metanephros induction defects.

1. Renal agenesis.

a. Defects in the inductive interaction between the ureteric bud and metanephric blastema may cause
renal agenesis.

b. In the absence of inductive signals from the ureteric bud, the metanephros fails to develop. Infants
with bilateral renal agenesis are stillborn or die within a few days after birth. If unilateral renal agenesis
occurs the remaining kidney will become hypertrophic to compensate for the missing kidney.

c. 75% of the cases involving renal agenesis occur in males.

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d. Renal agenesis typically causes other congenital defects. Since the kidneys initially contribute to the
production of amniotic fluid, bilateral renal agenesis results in oligohydramnios. The insufficient
amniotic fluid causes the uterine wall to compress the growing fetus, resulting in Potters syndrome
(deformed limbs and facial defectsreceding chin, low set ears, and parrot- beak nose).

e. Unilateral renal agenesis is usually associated with heart defects and constrictions of the
gastrointestinal tract.

2. Hypoplasia or dysplasia.

a. Subtle defects in the interaction between the ureteric bud and the metanephric blastema can result
in hypoplasia or dysplasia of the developing kidney.

b. Renal dysplasia! nephrons develop abnormally, consisting of primitive ducts lined by


undifferentiated epithelium which is surrounded by connective tissue.

C. Congenital polycystic kidney disease (ADPKD or ARPKD).

1. AD=Autosomal dominant

2. AR=Autosomal recessive

3. This disease is characterized by small multifocal lesions of the proximal convoluted tubules, and
dialation and cyst formation in the collecting system (leads to destruction of the surrounding renal
parenchyma)

4. ARPKD also results in severe abnormalities of the hepatic collecting ducts and biliary system.

D. Wilms tumor causes nephroblastoma and genetal system defects.

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Urogenital System Development


Genital System Development

I. The genital and urinary systems develop in close conjunction.

Review note: During the 5th week, the primordial germ cells migrate from the yolk sac via the dorsal
mesentery to the mesenchyme of the posteriror body wall (10th thoracic level) (Fig 10-11A). The
primordial germ cells induce cells in the mesonephros and adjacent coelomic epithelium to proliferate
and form the genital ridges (Fig 10-11B,C & 10-12).

A. Primitive sex cord development.

1. As mentioned above the primitive sex cords develop from mesonephros cells and coelomic
epithelium cells. During the 6th week, these cells invade the region of the presumptive gonads to form
the primitive sex cords which completely invest the germ cells (Fig 10-11B).
2. At this point the sex cords have a cortical and medullary regions. After the 6th
week these regions pursue different fates in the male and female.

B. Paramesonephric duct (Mullerian) development.


1. During the 6th week, a thickend region of coelomeic epithelium (from the third thoracic segment
caudally to the posterior wall of the urogenital sinus) undergoes craniocaudal invagination (Fig 1011B,C), forming the paramesonephric (mullerian) ducts just lateral to the mesonephric ducts in both
male and

female embryos.

2. These ducts are enclosed in the basement membrane of the adjacent mesonephric ducts.

3. The caudal tips of the paramesonephric ducts connect with the pelvic urethra (the tips adhere to
each other before they connect) just medial to the openings of the right and left mesonephric ducts,
while the superior ends form funnelshaped openings into the coelom.

4. Further development of the paramesonephric ducts will be discussed later in the lecture.

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C. Virtually identical male and female genital systems (before end of 6th week).

1. In both sexes, germ cells and sex cords are present in both the cortical and the medullary regions of
the presumptive gonads.

2. Complete mesonephric and paramesonephric ducts are present.


3. After the end of the 6th week the ambisexual or indifferent phase of genital development ends.
4. 7th week, the male and female systems follow diverging pathways.

II. Basis of sex differentiation.

A. Autosomes and Sex Chromosomes.

1. There is a total complement of 46 chromosomes, 22 pairs consist of matching, homologous


chromosomes called autosomes. The remaining two chromosomes are called the sex chromosomes
because they determine the sex of the individual.

2. XX individuals are genetically female and XY individuals are genetically male.


Although the pattern of sex chromosomes determines the choice between male and female
developmental paths, the subsequent phases of sexual development are controlled by both the sex
chromosome genes and by the hormones and factors encoded by the autosomes.

3. The sex-determining region of the Y chromosome (SRY) encodes a transcription factor that controls
the choice between the male and female developmental paths.

4. When SRY is expressed in the sex cord cells (in the indifferent phase) male development is triggered
(Fig 10-13).

5. Thus, femaleness is the default pathway unless maleness is actively induced.

III. Male genital (internal) development.

A. Sertoli cell differentiation in the medullary sex cords.

1. The SRY protein causes cells within the medullary region of the primitive sex cords to begin to
differentiate into Sertoli cells, while the cells of the cortical sex cords degenerate (Fig 10-13 & 10-14).

2. If SRY is absent the sex cords develop into ovarian follicles.

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3. 7th week! differentiating Sertoli cells organize to form the testis cords (Fig 1014). Also, the testis begins to round up, reducing its area of contact with the mesonephros (a feminizing
influence). As the testes continue to develop, the degenerating cortical sex cords become separated
from the coelomic epithelium by the tunica albuginea (intervening connective tissue).

4. At pubery! testosterone surge! the testis cords and associated germ cells become canalized and
differentiate into the seminiferous tubules. The distal testis cords develop lumina and differentiate into
a set of thin-walled ducts called the rete testis.

5. The tubules of the rete testis become connected with 5 to 12 residual mesonephric tubules. The
mesonephric ducts become the spermatic ducts or vasa deferentia (vas deferens, singular).

B. Anti-Mullerian hormone secretion by the pre-Sertoli cells.

1. As the Sertoli cells begin to differentiate in response to the SRY protein, they also begin to secrete
anti-Mullerian hormone (AMH) or Mullerian-inhibiting substance (MIS) (glycoprotein). The protein
region resembles the transforming growth factor-beta molecule which has been implicated in
mesoderm induction and angiogenesis.
2. 8th to 10th week!AMH causes the paramesonephric (mullerian) ducts to regress in the male (Fig 1013 &10-14).

3. Paramesonephric duct remnants go on to form the appendix testis and utriculus prostaticus in the
adult male. In female embryos, the paramesonephric ducts do not regress.

Note: Freemartin calves (female calves that shared a womb with a male twin). At the time they
postulated that some substance (now known as AMH) from the male circulated in the blood, causing the
female to be sterile (has ovaries, but lacks the derivatives of the paramesonephric ducts).

Clinical note: Some genetic male humans have persistant paramesonephric ducts because AMH
production is deficient or the paramesonephric ducts do not respond to normal AMH levels. This
indicates that paramesonephric duct regression is an active process rather than a cessation in growth.

4. 9th week! the SRY protein (expressed by the pre-Sertoli cells) also initiates a cascade that induces the
differentiation of mesenchymal cells within the genital ridges into testosterone-secreting Leydig cells (in
the testis) (Fig 10-13).

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5. The Leydig cells (endocrine cells) produce testosterone and this early secretion is regulated by
chorionic gonadotropin, secreted by the placenta (later in development the pituitary gonadotropins of
the male fetus take over control).

C. Differentiation of the mesonephric ducts of the male.


1. 8th to 12th week! the initial secretion of testosterone stimulates the

mesonephric ducts to transform into the spermatic ducts (vasa deferentia) (Fig
10-14).

2. The most cranial end of each mesonephric duct degenerates into the appendix epididymis.

3. The region of the vas deferens adjacent to the presumptive testis differentiates into the convoluted
epididymis.

4. During the 9th week, 5 to 12 mesonephric ducts in the region of the epididymis make contact with
the cords of the future rete testis. 3rd month, these epigenital mesonephric tubules actually unite with
the presumptive rete testis. After uniting the epigenital mesonephric tubules are then called the ductuli
efferentes. They provide a pathway from the seminiferous tubules and rete testis tubules to the vas
deferens.

5. The mesonephric tubules at the inferior pole of the developing testis


(paragenital mesonephric tubules) degenerate into the paradidymis.

D. Differentiation of the accessory glands of the male urethra.

1. Three accessory glands of the male genital system all develop near the junction between the
mesonephric ducts and the pelvic urethra (Fig 10-15).
2. 10th week! The glandular seminal vesicles sprout from the distal mesonephric duct near their
attachment to the pelvic urethra. The portion of the vas defenens (mesonephric duct) distal to each
seminal vesicle is called the ejaculatory duct.

3. 10th week! The prostate gland develops from a cluster of endodermal evaginations that bud from
the pelvic urethra (induced by dihydrotestoterone). The initial prostatic outgrowths form five solid

prostatic cords. By the 11th week, the cords develop a lumen and glandular acini (the surrounding
mesenchyme differentiates into the smooth muscle and connective tissue of the prostate) and by the
13th to 15th weeks, as the testosterone concentrations reach a high level, the prostate begins to
secrete.
4. 10th week! The paired bulbourethral glands sprout from the urethra (inferior to the prostate). The
mesenchyme surrounding the endodermal glandular tissue differentiates into the smooth muscle and
connective tissue of the bulbourethral gland.

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Note: The secretions of the seminal vesicles, prostate, and bulbourethral glands all contribute to the
seminal fluid that protects and nourishes the spermatozoa after ejaculation (not absolutely necessary
for sperm function).

IV. Female genital (internal) development.

A. Absence of a Y chromosome.

1. The female sex cord cells do not express SRY protein (they do not contain the Y chromosome/SRY
region) and thus do not differentiate into Sertoli cells. As a result, AMH, Leydig cells, and testosterone
are not produced. The formation of male structures are not induced, causing the embryo to follow the
default pathway of female development (Fig 10-16).

2. In genetic females, the primitive sex cords degenerate and the mesothelium of the genital ridge
forms secondary sex cords which invest the primordial germ cells to form the follicle cells of the ovary
(Fig 10-16).

Review note: The female germ cells enter meiosis, but further development is inhibited by the follicle
cells. In males, the pre-Sertoli cells inhibit germ cell development before they enter meiosis. In the
female fetus, the germ cells differentiate into oogonia and enter the first meiotic division as primary
oocytes. The follicle cells then arrest germ cell development until puberty. The close contact of the
genital ridge and mesonephros in females is important for inducing the initial stages of gamete
maturation.

B. Absence of AMH in the female embryo.

1. The mesonephric ducts and mesonephric tubules require testosterone for their development. Thus,
in the female, they rapidly disappear, forming two remnants, the epoophoron and paroophoron (found
in the mesentery of the ovary). Also, a scattering of tiny remnants called Gartner's cysts cluster near the
vagina (Fig 10-16, 10-17C)

2. The paramesonephric ducts develop uninhibited.

3. The wall of the pelvic urethra (where the growing tips of the paramesonephric ducts adhere) forms a
slight thickening called the sinusal tubercle (Fig 10-17A). While fusing with the sinusal tubercle the
caudal tips of the paramesonephric ducts fuse in a superior direction (3rd to 5th month), forming the
genital canal or uterovaginal canal (superior portion of the vagina and uterus) (Fig 1017B,C).

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4. The superior portions of the unfused paramesonephric ducts become the fallopian tubes (oviducts),
and the funnel-shaped superior openings of the paramesonephric ducts become the infundibula of the
oviducts (Fig10-16).
5. Also during the 3rd month, the thickening endodermal tissue of the sinusal tubercle in the posterior
urethra forms a pair of swellings called the sinuvaginal bulbs (gives rise to the inferior 20 percent of the
vagina)(Fig 10-17).

6. The vaginal plate (of unkown origin, occludes the most inferior region of the uterovaginal canal)
elongates and becomes canalized by a process of desquamation (cell shedding) to form the inferior
vaginal lumen (3rd to 5th month).

7. While the vaginal plate forms, the lower end of the vagina lengthens caudally until it reaches the
posterior wall of the definitive urogenital sinus (4th month) (Fig 10-17C).

8. An endodermal membrane temporarily separates the lumen of the vagina from the cavity of the
definitive urogenital sinus (vestibule of the vagina). After the
5th month, this membranes degenerates into the vaginal hymen.

V. External genitalia development.

A. Male and Female external genitalia develop from the same primordia (Fig 10-18A).
1. Early 5th week! the cloacal folds (a pair of swellings) develop on either side of the cloacal membrane
(Fig 10-18A). They meet anterior to the cloacal membrane, forming the genital tubercle (a midline
swelling).

2. The perineum (formed by the fusion of the urorectal septum and cloacal membrane during the 7th
week) divides the cloacal membrane into an anterior urogenital membrane and a posterior anal
membrane.

3. The clocal fold flanking the urogenital membrane is called the urethral fold (genital/urogenital fold)
and the fold flanking the anal membrane is called the anal fold (Fig 10-18A).

4. The labioscrotal swellings then appear on either side of the urethral folds (Fig
10-18A).

5. Male and Female genitalia are morphologically indistinguishable at this stage. The appearance of the
external genitalia is similar in male and female embryos through the 12th week.

6. These presumptive genital precursors develop into the male and female genital
structures (Table 10-1).

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B. Male external genitalia (Fig 10-18B).

1. The urogenital folds fuse and the genital tubercle elongates to form the shaft and glans of the penis.

2. The perineal region separating the definitive urogenital sinus from the anus begins to lengthen (does
not occur in females).

3. Fusion of the urogenital folds encloses the definitive urogenital sinus to form most of the penile
urethra (enclosed by 14 weeks). An alternative mechanism of closure has been proposed in which the

penile urethra is enclosed by an anterior growth of perineal mesoderm (no involvement of the genital
folds).
4. 6th week! the extending cavity of the definitive urogenital sinus meets with the enlarging genital
tubercle, forming an endodermal-lined urethral grove (Fig 1018B). The grove eventually forms a temporary urethral plate (solid endoderm) which recanalizes to
form a deep groove. In males, the groove is long and broad. In females, the groove is short and
tapered.

5. A small region of the distal urethra is formed by the invagination of the ectoderm covering the glans.

6. The labioscrotal folds give rise to the scrotum.

C. Female external genitalia (Fig 10-18C).

1. Since there is no dihydrotestosterone in female embryos, the primitive perineum does not lengthen
and the labioscrotal and urethral folds do not fuse across the midline (Fig 10-18C).

2. The phallus (elongated genital tubercle) bends inferiorly, becoming the glans and shaft of the clitoris
(Fig 10-18C).

3. The definitive urogenital sinus becomes the vestibule of the vagina.

4. The urethral (urogenital) folds remain separated to form the labia minora, and the labioscrotal folds
(swellings) become the labia majora.

VI. The gubernaculum controls the descent of the testes and ovaries.

A. Gubernaculum.
1. Both testes and ovaries descend from the 10th thoracic level. The testes eventually descend much
farther than the ovaries.

2. In both sexes, the descent of the gonad depends on a ligamentous cord called the gubernaculum.
3. 7th week! the gubernaculum condenses within the subserous fascia of a longitudinal peritoneal fold
on ether side of the vertebral column (Fig 10-19).

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4. The superior end of the gubernaculum attaches to the gonad and the inferior end (gubernaculum
bulb) attaches to the fascia in the region of the labioscrotal swellings.
5. 8th week, the processus vaginalis or vaginal process (evagination of the peritoneum) develops just
adjacent to the inferior root of the gubernaculum.

6. In males, the inguinal canal is formed when the vaginal process pushes out a socklike evagination of
the abdominal wall. The vaginal process pushes through the transversalis fascia (gives rise to the
internal spermatic fascia of the spermatic cord), the internal oblique muscle (gives rise to the
cremasteric fascia of the spermatic cord), and the external oblique muscle (becomes the external
spermatic fascia). As the vaginal process elongates caudally it brings along the bulb of the
gubernaculum. Eventually, the vaginal process degenerates.

B. The descent of the testes (Fig 10-19).

1. In the male the inguinal canal extends into the scrotum and transmits the descending testes. In
females a complete inguinal canal also forms, but it does not play a role in female genital development.

2. The inguinal canal is considered as a series of weakenings (deep ring weakening of the transversalis
fascia and the superficial ringweakening of the external oblique muscle) in the layers of the abdominal
wall (Fig 10-19D). These stretched out layers allow the testes to descend into the scrotum.

3. The testes descend to the deep ring of the inguinal canal by the third month and complete their
descent in the seventh to ninth months.

4. 7th to 12th weeks, the extrainguinal portions of the gubernacula shorten (first phaseshorten by
getting flatter at their base) and pull the testes down to the deep ring (enlarges the inguinal canal). The
testes remain in the vicinity of the deep ring from the 3rd to 7th month.
5. 7th to 9th month, second phase of shortening occurs by actual reduction and regression of the
gubernaculum (testosterone and other androgens are important for the second phase). The descent of
the testes is also aided by the increased abdominal pressure (which results from the growth of the
abdominal viscera).

Clinical note: The superior region of the vaginal process degenerates leaving a distal remnant called the
tunical vaginalis (anterior to the testis) (Fig 10-20 & Fig 10-21). Normally the lumen is collapsed, but
under pathologic conditions it may fill with serous secretions, forming a testicular hydrocele (Fig 10-20B,

D). Also, occasionally the entire vaginal process remains, forming an indirect inguinal hernia (connection
between the abdominal cavity and the scrotal sac) (Fig 10-20C). Inguinal hernias also can occur in
females. Repair of these hernias is the second most common childhood operation.

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Dr. Martinsen

DENT 5315/OBIO-8024

January 16, 2007

C. The descent of the ovaries (Fig 10-22).

1. The female embryo also forms a gubernaculum. It is attached at the inferior pole of the gonad and
extends to the presumptive labioscrotal folds and abdominal wall (this forms the female inguinal canal).

2. In the female, the gubernaculum does not shorten or regress, but it still causes the ovaries to
descend during the 3rd month, sweeping them into the broad ligament of the uterus (Fig 10-22 & Fig 1017). The ovaries move because the paramesonephric ducts (which are attached to the gubernaculum)
fuse and pull the broad ligaments into the peritoneal folds.

3. The inferior gubernaculum becomes the round ligament of the uterus


(connects the fascia of the labia majora to the uterus).

4. The superior gubernaculum becomes the ligament of the ovary (connects the uterus to the ovary).

VII. Clinical Applications.

A. Variable phenotypes of Wilms Tumor.

1. Denys-Drash syndrom (DDS)!severe abnormalities of the gonads and external genetalia.

2. WAGR syndrome!Wilms tumor, aniridia (lack of irises), genital abnormalities, and mental
retardation.

3. Beckwith-Wiedemann syndrome!renal hyperplasia and Wilms tumor (individuals lack the normal
genomic imprinting that inactivates the IGF-2 gene on the paternal chromosome.

B. Defective partitioning of the cloaca.

1. Failure of the Rathke fold to develop (Rectourethra fistuals) (Fig 10-26)!In males, they form a
rectoprostatic urethral fistula (Fig 10-26C). In females, a rectocloacal canal (Fig 10-26D), a rectovaginal
fistula (Fig 10-26E), or an anovestibular fistula can form.

2. Failure of both Rathke and Tourneux fold development!causes a more severe defect in which the
rectum and the bladder are connected (rectovesical fistula) (Fig 10-27).

3. Malalignment of the Tourneux and Rathke folds! results in a urorectal fistula (Fig 10-28).

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Dr. Martinsen

DENT 5315/OBIO-8024

January 16, 2007

C. Anal malformations (result form maldevelopment of the anal pit, anal membrane or genital folds).

1. Anal agenesis (Fig 10-29A)!causes rectum to end blindly in the body wall.

2. Imperforate anal membrane! caused by a thickened anal membrane that failed to rupture (Fig 1029B).

3. Anal stenosis! caused by an incomplete rupture of the anal membrane.

D. Abnormal development of the genital system.

Note: Most genital system malformations arise from alterations in autosomal genes.

1. Pseudohermaphroditism (external genitalia of one sex accompany the gonads of the other)! caused
by sex hormone anomalies. The block of which male hormone would cause external genital
feminization?

2. The most common manifestation of male pseudohermaphroditism is hypospadias (urethra opens


onto the ventral surface of the penis (Fig 10-30A, B). A more complex condition (penoscrotal
hypospadias) occurs when the labioscrotal swellings, as well as the urethral folds fail to fuse (urethra is
open through a hole between the base of the penis and the root of the scrotum) (Fig 130C,D). The block of which hormone, dihydrotestosterone or testosterone, results in perminant
feminization of the male genitalia? Why?

3. Testicular feminization syndrome! the androgen receptors are abnormal, resulting in the formation
of a blind-ending vagina. Since the testes are still present and AMH is produced, the paramesonephric
ducts regress.

4. Female pseudohermaphroditism! is very rare. These individuals exhibit clitoral hypertrophy and
fusion of the urethral and labioscrotal folds. Because the testes and AMH are absent the vagina, uterus ,
and fallopian tubes develop normally.

5. True hermaphrodites have both ovarian and testicular tissue. The gonads are usually a composite
ovotestes containing both seminiferous tubules and follicles. Or an individual may have an ovary on one
side and a testes on the other side. Most true hermaphrodites are reared as males since a phallus is
usually present at birth.

6. Primary hypogonadism! is caused by a gonadal defect. The gonads do not respond to the
gonadotropins and thus do not increase production of sex steroids at puberty. Thus the individual fails
to enter puberty. In males, primary hypogonadism is usually caused by Klinefelter syndrome (extra X
chromosome). In females, primary hypogonadism is usually associated with Turner syndrome (missing X
chromosome).

7. Secondary hypogonadism! is caused by defects of the hypothalamus or anterior pituitary. These


individuals have depressed levels of both gonadotropins and sex steroids and thus do not enter puberty.

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