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Neurulation
During gastrulation, a population of the dorsal ectoderm is specified to become neural ectoderm
Involves signals: Noggin, chordin, follistatin [Organizer Signals]
Cells become columnar in their appearance Neural plate
The neural plate will be induced to form a hollow neural tube = spinal cord, brain, etc.
Neural Fate
Organizer secretes growth factor
anatagonists
Default state of dorsal ectoderm
Neural, not epidermal [alternative]
BMP prevents this neural fate
The organizer blocks BMP (and
Wnt and Nodal) via noggin,
chordin and cerberus, dickkopf
Reason you get skin is because of
BMP
Neural Induction
FGFs work in concert with BMP and WNT inhibitors
Activate neural genes
Erni,Otx2 and Sox1/3
BMP, Wnt are from lateral regions
Inhibitors are from medial regions
Neural tube is a medial structure
Mediolateral gradient of WNT and BMP activity
1
Neural plate border cells originate within a zone exposed to intermediate levels of WNT and BMP
activity
2
Neurulation in
Mammals
Neural tube closes in several places along axis (not in A to P direction)
If any one of those closures fails, neural defects result
Mammalian Neural Tube Defects
Spina Bifida
Posterior Neural tube does not fuse
Spinal cord remains exposed
Linked to follic acid
Anencephaly
Anterior Neural tube does not fuse
Forebrain ceases to develop
Occur in 1 of 500 births in humans
Differentiation of the Neural Tube [Notochord incorporated as vertebral disk]
Neural tube must maintain dorsal-ventral polarity
Sensory neurons – dorsal
Motor neurons – ventral
Accomplished by “inductive cascades”
Dorsal: BMPs (TGF-Beta structure) from epidermis
Roof plate cells in neural tube
TGF-B cascadeCell differentiation
Ventral: Sonic hedgehog from notochord and retinoic acid from somites
Floor plate cells of neural tube
Shh gradient Cell differentiation
3
Overview of Neural Crest
Neural crest is a stem/progenitor cell
population that contributes to a wide
variety of derivatives
Sensory and autonomic ganglia,
cartilage and bone of the face and
pigment cells of the skin
Neurons in the gut system
Unique to vertebrate embryos
Ability to migrate extensively and
differentiate into numerous
derivatives
Important in the formation of
structures
‘Fourth germ layer’
Neural Crest Derivatives
The beak is a neural crest derivative
The large head shield and bony
horns of Triceratops were derived from the neural crest
The mesenchyme of the tail fin and also the pigment cells in this fish are derived from neural crest
cells
A mandrill
The contours and colours of its face are mainly produced by the neural crest cells
The blue colouration is due to the presence of melanophores in the skin
Neural Crest Cell Role
Julia Platt
Discovered in 1893 that NCCs contribute to structures in the cranium of mudpuppies
Contradicted the germ layer theory, which described the mesoderm as the germ layer that
was the only progenitor of the craniofacial skeleton
Neural Crest Development
Induced in the ectodermal germ layer during gastrulation
Reside in the neural plate border territory
Border territory elevates
Come to reside within the dorsal aspect of the opposing neural folds
Specification
4
FoxD3, Sox10
Slug and FoxD3 in Neural Crest Formation
FoxD3
If inhibited, no neural crest cells form
Thus, necessary for neural crest specification
Slug
If inhibited, neural crest cells cannot migrate
Thus, necessary for neural crest migration
Msx Snail Sox10 Slug
Snail
Snail 1/2 has been linked to Epithelial to Mesenchymal Transition (EMT) in many systems, from
cancer cell lines to gastrulating embryos
In the neural crest
Snail 1/2 functions as a transcriptional repressor
Downregulation of the type 1 cadherins during EMT
NCAD repression
Sox9 interacts with Snail 1/2 to drive EMT
Neural Crest: 4 Domains
(1) Cranial (Cephalic) Neural Crest
Cartilage, bone, cranial neurons, glia and connective tissues of the face, bones of middle ear,
jaw, tooth primordia
Derivatives – R = Rhombomere
From midbrain and R1,2
Migrate to 1st branchial arch
Face tissues: bone, cartilage, dermis, dentine, eye
Jaw bones, incus, malleus
Trigeminal nerve
No Hox expression
From R4
Migrate to 2nd arch
Hyoid cartilage, stapes, facial nerve
Hox2
From R6,8
Migrate to 3rd , 4th arches
Thymus, parathyroid, thyroid
(2) Trunk Neural Crest
Dorsal root ganglia and sensory neurons,
sympathetic ganglia of SNS, melanocytes - all pigment cells of body
2 Pathways of Migration
(A) Dorsolateral Pathway
Between epidermis and somites
Gives rise to Melanocytes
(B) Ventral Pathway
Through Sclerotome (Anterior half only)
Gives rise to dorsal root ganglia, sympathetic ganglia, & adrenal medulla [secrete
epinephrine] [Sympathetic Nervous System]
Specifiers
Sensory neurons — BDNF
5
Autonomic neurons — BMP
Melanocytes and enteric neurons — Endothelin3
Schwann cell — Neuregulin
Smooth muscle — TGF-beta
(3) Vagal and Sacral Neural Crest
Parasympathetic nerves of gut
(4) Cardiac Neural Crest
Melanocytes, neurons, division between aorta & pulmonary artery
Chondrocytes
Cranial neural crest cartilage model
Gives rise to Craniofacial skeleton
Quadrate, Meckel’s cartilage, surrounding membrane bones, cartilage of the tongue
Membrane bones of the jaw and skull
Large percentage of birth defects
Sox9, Agc1 (marker for cartilage)
Sox9must be shut down in order to prevent cartilage formation [Cartilage to bone]
Sox9 marks chondrocytes
Hox Genes and Cell Fates [Left] & Derivates of the P. Arches [Right
Neurocristopathies
Abnormal expression, migration, differentiation, or death of neural crest cells during embryonic
development
Albinism (piebaldism) and cleft palate
Various pigment, skin, thyroid, and hearing disorders, craniofacial and heart abnormalities,
malfunctions of the digestive tract, and tumors
Abnormal functioning of the Hox genes
Hirschsprung Disease
Sox10 Mutations
The neural crest fails to migrate to the gut
Absence/sparsity of neurons in the gut
Matter gets collected in the colon
Waardenburg Syndrome
PAX3, MITF, or SNA12 Mutations
Faulty hair pigmentation, eye pigmentation, etc.
Notes
6
Neural Crest Final Product = Based on HOX Expression
Neural Crest leave [with HOX expression] Migrates toward the arches and influence the arches