BIOLOGY 30 LEC

Professor Elisa L. Co, PhD

Cell Interaction during Organogenesis –

26.February.2009
“halimbawa sa high society, ayaw nilang ung
asawa ng anak nila common tao”

Outline
I. Proximate Induction (Secondary
Induction)
A. Components
B. Types of Secondary Induction
C. Modes of Induction
D. Epithelio-mesenchymal Induction

II. Cell-to-Cell Communication

Proximate Induction
Recall: Primary Induction – @ the dorsal lip of the Optic vesicle induces ectoderm to become lens
blastopore, Spemann’s organizer vesicle, therefore ectoderm must be competent
versus in order to respond
Secondary (proximal) Induction – one group of Without optic vesicle, no induction
cells changing the behavior of an adjacent set of  Something other than optic vesicle, no
cells thereby causing them to change the shape, induction
mitotic rate or fate
e.g. neural tube and neural ectoderm Competence: ability to respond to a specific
* may induce a change in morphology or activity inductive signal
- not a passive state but an actively acquired
A. Components condition
1.Inducer – the tissue that produces a signal
or signals that changes the cellular behavior Competence Theory – tested by a recombinant
of other tissues experiment
2.Responder – inducee; the one affected The Experiment: used Pax-6 protein, testing eye
develop’t
The Signal: Pax-6 protein – required in dev’t of
mammalian and avian eye to make ectoderm
competent to respond to inductive signal from
optic vesicle
The Results:
HOWEVER, (a) abnormal surface ectoderm (pax-6 –
Not all tissues homozygous mutant) + wild type (normal)
can respond to a = no lens vesicle
signal (e.g. Lens (b) wild type ectoderm + mutant optic vesicle
Induction) = no vesicle
The Findings: Pax-6 causes the responder to
produce whatever desired effect.

B. Types of 2ndary Induction

1.Reciprocal – occurs when two interacting
tissues are both inducer and competent to
respond to each other’s signals (ex. Lens
vesicle sending signals to optic vesicle to
differentiate)
2.Sequential – cascade of events brought
about by many tissues simultaneously
(parang intersection: may papasok, may palabas,
may galing sa inner road =P)

Biology 30 lecture - Casilang, Gilbuena, Leones, Magbuhat, Page 1 of 5

26.Feb.09 Sagayaga
BIOLOGY 30 LEC
Professor Elisa L. Co, PhD

Cell Interaction during Organogenesis –

26.February.2009
**inducer can later become responder, and vice- D. Epithelio-Mesenchymal Inductions (most
versa studied)
(

–
–

- example of reciprocal induction (between the

Sequential inductive events and multiple causes epidermis and the dermal mesenchyme)
each induction. This is responsible for organ
formation.
Regional Specificity
C. Modes of Induction - depends on the source of the dermal
1.Instructive Interaction – a signal from the mesenchyme, w/c is responsible for regional
inducing cell is necessary for initiating a specificity of induction in the competent
new gene expression in the responding cell. epidermal epithelium.
 Without the inducing cell, the responding - the same type of epithelium develops cutaneous
cell would not be capable of differentiating structures according to the region from w/c the
in that particular way. mesenchyme was taken
Three Main Principles:
1.In the presence of tissue A, responding
tissue B develops in a certain way.
2.In the absence of tissue A, responding
tissue B does not develop in that way.
3.In the absence of A, but in the presence
of tissue C, tissue B does not develop in
that way.

2.Permissive Interaction – the responding

tissue contains all the potentials that are to
be expressed, and needs only an
environment that allows the expression of
these traits
Signals are overruled by the environment.
(Milieu must allow the expression of traits.)
e.g. Solid substrate containing fibronectin
or laminin
- it does not alter the type of cell that is to
Genetic Specificity
be prouced, but only enables what’s been
- whereas the mesenchyme may instruct the
determined to be expressed. (recall
epithelium as to what sets of genes to activate
gastrulation)
the responding epithelium, the responding
Biology 30 lecture - Casilang, Gilbuena, Leones, Magbuhat, Page 2 of 5
26.Feb.09 Sagayaga
BIOLOGY 30 LEC
Professor Elisa L. Co, PhD
Cell Interaction during Organogenesis
26.February.2009
epithelium can comply with these instruction as
long as its genome permits.
Interspecific Induction
The Experiment: The ectoderm of a frog gastrula
was placed into the prospective mouth region
of the newt gastrula.
The Results:
(a) Newt with tadpole suckers and horny jaw
with no teeth
(b) Tadpole with newt balancers with
calcareous teeth
The Findings: Instruction can cross species
barrier, but the response is species-specific.
Thus it is the epidermis w/c determines the
kind of organ formed based on its genetic
message.
Cell-to-Cell Communication
 (Reading Assignment from Gilbert)
Juxtacrine Factors – proteins on the cell surface
interact with receptors on adjacent surfaces.
versus
Paracrine Factors (or growth and differentiation
factors) – diffusible proteins synthesized by one
cell that travel small distances to induce changes
in neighboring cells.
- secreted by cells into the space surounding
them (as opposed to blood-borne endocrine
factors)
- “inducing factors” of classical embryologists
- grouped into four major families:
(a) Fibroblast Growth Factors (FGFs) Family
(b) Hedgehog Family
(c) Wingless (Wnt) Family
Biology 30 lecture - Casilang, Gilbuena, Leones, Magbuhat,
26.Feb.09 Sagayaga
–
(d) TGF-β Superfamily
1. FGF Family
- has over a dozen structurally related members
e.g. FGF1 (acidic FGF); FGF2 (basicFGF); FGF7
(keratinocyte growth factor)
- can generate hundreds of protein isoforms by
varying their RNA splicing or initiation codons in
different tissues
Developmental Functions
angiogenesis, mesoderm formation and axon
extension
Fibroblast Growth Factor Receptors (FGFRs)
- a set of receptor tyrosine kinases which are
proteins that extend through the cell membrane.
extracellular side: portion of the protein that
binds the paracrine factor
intracellular side: a dormant tyrosine kinase
(i.e., a protein that can phosphorylate
another protein)
The Pathway
1. FGF receptor binds an FGF
2. The dormant kinase is activated and it
phosphorylates certain proteins within the
responding cell.
3. The proteins are now activated and can
perform certain functions.
2. Wnt Family
Wnt
- constitute a family of cysteine-rich glycoproteins
Developmental Functions
- establishing the polarity of insect and vertebrate
limbs
- used in several steps of urogenital system
development
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BIOLOGY 30 LEC
Professor Elisa L. Co, PhD

Cell Interaction during Organogenesis –

26.February.2009
examples:
Wnt 1 - induce the dorsal cells of the somites to
become muscles
GSK-3 - metabolic enzyme which regulates
glycogen metabolism.
β-catenin - part of the cell-adhesion complex of
the cell surface, also a transcription factor
APC protein - tumor suppressor in adults
The Pathway
evident principle in the pathway: activation is
often established by inhibiting an inhibitor.
e.g. Wnt suppressing GSK-3
1. Members of the Wnt family interact with
transmembrane factors of the Frizzled family.
2. The Frizzled protein activates the Disheveled
protein.
3. The activity of glycogen synthase kinase-3
enzyme (GSK-3), which prevents the
dissociation of β-catenin protein from the APC
protein, is inhibited. This inhibition prevents
β-catenin degradation.
4. β-catenin can now enter the nucleus. This can
form a heterodimer with an LEF or TCA-
binding protein, becoming a transcription
factor.
5. The complex then binds to and activates the
Wnt-responsive genes.
- induce particular cell types and create
boundaries between tissues
Three Types: SHH, IHH, and DHH
1. SHH – Sonic Hedgehog
- most widely used, produced by the
notochord
- responsible for patterning the neural tube
and somites
- mediates the formation of the left-right axis
in chicks
- initiates the antero-posterior axis in limbs
- induces the regionally-specific differentiation
of the digestive tube
- induces feather formation
2. IHH – Indian Hedgehog
- expressed in the gut and in the cartilage
- important in postnatal bone growth
3. DHH – Desert Hedgehog
- expressed in the Sertoli
Cholesterol
- critical for the catalytic cleavage of the SHH
protein
- Patched protein that binds the SHH protein
needs cholesterol in order to function
Without the Hedgehog:
• The Patched protein prevents the
Smoothened protein from functioning.
• The Cubitus Interruptus (Ci) is tethered to
the microtubules of the surrounding cell.
• In the microtubules, Ci is cleaved in such a
way that a portion of it enters the nucleus
and acts as transcriptional repressor by
binding to promoters and enhancers of
particular genes.
The Pathway
notable feature: the important involvement of
cholesterol.
1. The hedgehog family binds to a receptor
called Patched, which is bound to a signal
transducer, the Smoothened protein. * The
Smoothened protein acts (probably by
phosphorylation) to release the Ci (Cubitus
interruptus)
2. The intact Cican now enter the nucleus, where
it acts as a transcriptional activator of the
same genes it used to repress

3. Hedgehog Family

Developmental Functions

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26.Feb.09 Sagayaga
BIOLOGY 30 LEC
Professor Elisa L. Co, PhD

Cell Interaction during Organogenesis –

26.February.2009
2. Binding of the ligand causes, conformational
changes and autophosphorylation of the
receptor’s cytoplasmic domain
3. Phosphorylated tyrosine on the receptor is then
recognized by an adaptor protein (bridge that
links the phosphorylated RTK to a powerful
intracellular signaling system)
4. Adaptor protein also activates a G protein
(usually inactive state)
5. The activated receptor stimulates the adaptor
protein to activate the guanine nucleotide
releasing factor (exchanges a phosphate from a
GTP to transform the bound GDP into GTP)
6. After delivering the signal, the GTP on the G
protein is hydrolyzed back into GDP (greatly
stimulated by the complexing of the Ras protein
with the GTPase-activating protein (GAP))

MEK- a kinase w/c activates ERK by

4. TGF-β superfamily
phosphorylation
- includes the TGF-β family, activin family, the
ERK- a kinase w/c can enter the nucleus and
BMPs, the Vg1 family and glial-derived
phosphorylate certain transcription factors.
neurotropic factors
*In the migrating neural crest cells of humans
Developmental Functions
and mice, the RTK pathway is important in
1. TGF-β1,2,3 and 5
activating the microphthalmia transcription factor
- important in regulating extracellular matrix
(Mitf) to produce the pigment cells.
formation between cells (for regulating cell
division)
The Smad pathway
- can compensate for the losses of the others
1. The TGF-β ligand binds to a type II TGF-β
TGF-β1 - increases amount of extracellular
receptor, which allows that receptor to bind to a
matrix
type I TGF-β receptor
2. BMP family
2. the type II receptor phosphorylates a serine or
- induces bone formation
threonine on the type I receptor, thereby
- regulates cell division, apoptosis, cell migration
activating it
and differentiation
3. The activated type I receptor can now
Nodal - protein responsible for L and R axis
phosphorylate the Smad proteins.
formation
BMP4 - neural tube polarity, eye
- Smads 1 and 5- activated by the BMP family of
development and cell death
TGF-β factors
- Receptors binding activin and the TGF-β family
Cell Surface Receptors and their Signal
phosphorylate Smads 2 and 3
Transduction Pathways
- In vertebrates, the TGF-βsuperfamily ligand
Nodal appears to activate the Smads pathway in
Signal Transduction Pathways
those cells responsible for the formation of the
- pathways between cell membrane and the
mesoderm and for specifying the left-right axis in
genome
vertebrates
*Each receptor has an extracellular region, a
transmembrane region and a cytoplasmic region

The RTK pathway

- begins at the cell surface, where a Receptor
Tyrosine Kinase (RTK) binds its specific ligand.
1. Ligands: FGFs, EGFs, platelet-derived growth
factors and stem cell factors
Biology 30 lecture - Casilang, Gilbuena, Leones, Magbuhat, Page 5 of 5
26.Feb.09 Sagayaga
BIOLOGY 30 LEC
Professor Elisa L. Co, PhD

Cell Interaction during Organogenesis –

26.February.2009

SMAD Pathway

The JAK-STAT pathway

1. The set of transcription factors consists of the
STAT (signal transducers and activators of
transcription) proteins
2. Extremely important in the differentiation of
blood cells , regulation of human fetal bone
growth and in the activation of the casein gene
during milk production
3. Endocrine factor prolactin binds to the
extracellular regions of prolactin receptors,
causing them to dimerize
4. JAK protein kinase is bound to each of the
receptors
5. JAK proteins convert a receptor into a receptor
tyrosine kinase

*thanatophoric dysplasia- a severe form of dwarfism

caused by premature activation of JS pathway (the
growth plates of the
rib and limb bones fail to proliferate)

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26.Feb.09 Sagayaga