CELL-CELL COMMUNICATION IN

DEVELOPMENT

LEE KUI SOON

 Cell-Cell Communication
Concepts:
Cells develop in the context of their environment, including:
-their immediate cellular neighborhood
-their tissue identity
-their position in the body.
Developing cells receive signals from each of these locations,
and they, in turn, signal the cells around them.
1) A signal
2) A receptor for that signal
3) A mechanism to translate and/or transport the signal
4) A mechanism to translate the signal to a stimulation
(or repression) of gene expression
LEE KUI SOON
 How do cells interact or communicate?

How are the signals between inducer and responder transmitted?

The interaction at close range between two or more cells or
tissue of different history or properties is called proximate
interaction or induction.

This inductive interaction involves at least two

Components:
1. Inducer
2. Responder

The ability to respond to a specific inductive signal is

called competence

LEE KUI SOON

Vertebrate Eye Development-Induction
Induction- Vertebrate Eye Development
Induction and Competence
 Inducers

Inducers are molecular components; e.g. optic vesicle

inducers:
BMP4 (bone morphogenic protein 4)
- induces Sox2 and Sox3 transcription factor

 Fgf8 (fibroblast growth factor 8)

- induces L-Maf transcription factor
Stepwise Induction
Reciprocal Induction
Pax6 expression the rat embryos
WT Pax6 -/-

WT Pax6 -/-
 Competence Factor

Competence -ability of a cell or tissue

to respond
to a specific inductive signal
-actively acquired (and can also be
transient) Pax6

During lens induction Pax6 is expressed

in the head ectoderm, but not in other
regions of surface ectoderm

Pax6 is a competence factor for lens Pax6

induction
 Cascade of induction

Reciprocal and Sequential events:

Once a type of tissues are formed, it can then

induced the formation of other tissues

The formation of mouse lens could secrete other

factors to induced the formation of optic cup,
the wall of the optic cup then differentiates
into pigmented retina and retina neuron. This
Interactions are called reciprocal inductions

LEE KUI SOON

 Instructive and Permissive Interactions

Instructive interaction
-a signal from the inducing cell is necessary for
initiating new gene expression in the responding cell

3 general principles characteristic of most instructive

interactions:
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 tissue A, but in the presence of
tissue C, tissue B does not develop in that way
LEE KUI SOON
 Instructive and Permissive Interactions

Permissive Interactions

Responding tissue contains all the potentials that are

to be expressed and needs only an environment that
allows the expression of these traits

For instance, many tissues need a solid substrate

containing fibronectin or laminin to develop but both
(fibronectin or laminin) does not alter the type of cell
that is to be produced, but only enables what has
been determined to be expressed

LEE KUI SOON

 Cell-Cell Communication
Concepts:
Cells develop in the context of their environment, including:
-their immediate cellular neighborhood
-their tissue identity
-their position in the body.
Developing cells receive signals from each of these locations,
and they, in turn, signal the cells around them.
The components of this signal/response system must
include:
1) A signal
2) A receptor for that signal
3) A mechanism to translate and/or transport the signal
4) A mechanism to translate the signal to a stimulation
(or repression) of gene expression
LEE KUI SOON
 Inducing Signals

See also: autocrine (self-generated) signals and endocrine signals

LEE KUI SOON

 Paracrine Factors
Paracrine factors
When proteins synthesized by one cell can diffuse over small
distances to induce changes in neighboring cells, this event
is called paracrine interaction and the diffusion proteins are
called paracrine factors or growth differentiation factors

4 major families:
1. Fibroblast Growth Factor (FGF)
2. The Hedgehog family
3. The Wingless (Wnt) family
4. TGF-β superfamily (TGF = Transforming Growth Factor)
-TGF- β family
-Activin family
-Bone morphogenic proteins (BMPs)
-Vg1 family
LEE KUI SOON
 Fibroblast growth factor (FGF)
Can activate a set of fibroblast growth factor receptors
(FGFRs)

When the FGF receptor binds an FGF (and only when it

binds an FGF), the dormant kinase is activated, and it
phosphorylates certain proteins within the responding cell.
The proteins are now activated and can perform new functions

FGFs are associated with several developmental functions,

including angiogenesis (blood vessel formation), mesoderm
formation, and axon extension. While FGFs can often
substitute for one another, their expression patterns give
them separate functions. FGF2 is especially important in
angiogenesis, and FGF8 is important for the development of
the midbrain and limbs
LEE KUI SOON
Signal Transduction: FGF expression
Structure of a
receptor tyrosine
kinase. The
dormant tyrosine
kinase is activated
by the binding of
FGF by the
extracellular
portion of the
receptor protein.
This enzyme activity
phosphorylates
specific tyrosine
residues of certain
proteins
LEE KUI SOON
 The Hedgehog family

• used by the embryo to induce particular cell types and to

create boundaries between tissues

• responsible for patterning the neural tube such that motor

neurons are formed from the ventral neurons and sensory
neurons are formed from the dorsal neurons

• responsible for patterning the somites so that the portion

of the somite closest to the notochord becomes the cartilage
of the spine

LEE KUI SOON

 The Hedgehog family

• shown to mediate the formation of the left-right axis in

chicks, to initiate the anterior-posterior axis in limbs, to
induce the regionally specific differentiation of the digestive
tube, and to induce feather formation

• works with other paracrine factors, such as Wnt and FGF

proteins. In the developing tooth, Sonic hedgehog, FGF4,
and other paracrine factors are concentrated in the region
where cell interactions are creating the cusps of the teeth

• Desert hedgehog and Indian hedgehog are used postnatally

to regulate bone growth and sperm production

LEE KUI SOON

 The Wnt family

• bind to receptors of the Frizzled and LRP families on the

cell surface
• active in inducing the dorsal cells of the somites to become
muscle
• critical in establishing the polarity of insect and vertebrate
limbs, and they are used in several steps of urogenital
system development

LEE KUI SOON

The Wnt family

LEE KUI SOON

 The TGF-β superfamily

• are important in regulating the formation of the extracellular

matrix between cells and for regulating cell division
(both positively and negatively)

• increases the amount of extracellular matrix epithelial cells

make (both by stimulating collagen and fibronectin synthesis
and by inhibiting matrix degradation)

• critical in controlling where and when epithelia can branch

to form the ducts of kidneys, lungs, and salivary glands

LEE KUI SOON

 Juxtacrine Signaling

• proteins from the inducing cell interact with

receptor proteins of adjacent responding cells
• The inducer does not diffuse from the cell
producing it
• Refer to Notch pathway
 Juxtacrine Signaling

THREE types of juxtacrine interactions

I. a protein on one cell binds to its receptor on the
adjacent cell
II. a receptor on one cell binds to its ligand on the
extracellular matrix secreted by another cell
III. the signal is transmitted directly from the
cytoplasm of one cell through small conduits into
the cytoplasm of an adjacent cellacellular matrix
secreted by another cell
Cell surface receptors and their
signal transduction pathway

LEE KUI SOON

 Signal Transduction

Extracellular signals are received at the membrane and then

transduced to the cytoplasm at the cell membrane
-external signal is transmitted into the interior of the cell
e.g. receptor tyrosine kinase (RTK)
(kinase = enzyme that phosphorylatesa protein)

Signal transduction cascades

-most intercellular and intracellular signals are part of larger
sets of pathways
-activated products or intermediates trigger other pathways

e.g. receptor tyrosine kinase (RTK)

(kinase = enzyme that phosphorylatesa protein)
LEE KUI SOON
The RTK pathway
1. Ligand binding
2. RTK dimerized
3. RTK autophosphorylation
4. Adaptor protein binding
5. GNRP binding
6. GNRP activates Ras
(G protein)
7. Ras-GDP → Ras-GTP
8. GAP recycles Ras
9. Active Ras activates Raf
(protein kinase C;PKC)
10. Raf phosphorylates
MEK (a kinase)
11. MEK phosphorylates
ERK (a kinase)
12. ERK phosphorylates
(transcription factors)
13. Transcription modulation

LEE KUI SOON

 JAK-STAT Pathway
JAK–Janus kinase
-non-receptor tyrosine kinase

STAT–Signal Transducers and

Activators of Transcription

-transcription factor
Pathway activators:
prolactin, cytokines,
growth hormones;
-cell proliferation
-differentiation
-apoptosis
NOTE
–STATs can be
activated independently
of JAKs
-RTK; e.g. EGF receptor
-non-receptor tyrosine
kinases; e.g. c-src
LEE KUI SOON
 Hedgehog Pathway : Generic

Drosophila

LEE KUI SOON

Wnt Pathway :Canonical
APC -adenomatosispolyposiscoli
(tumor suppressor)-targets β-catenin
for degradation

GSK-3 -Glycogen synthase kinase 3

-prevents β-catenin dissociation from
APC

Wnt binds to Frizzled receptor family

-activates Disheveled
-Disheveled blocks GSK-3
-β-catenin released from APC
-enters nucleus
-associates with LEF/TCF TFs

NOTE -actual picture more complex;

many other possible participants; e.g.-at
surface -co-receptors, etc.-cytoplasmic -
G-protein, other actors
LEE KUI SOON
Wnt Pathway

LEE KUI SOON

SMAD Pathway

LEE KUI SOON

Proto-oncogene

LEE KUI SOON

Notch Signaling

LEE KUI SOON

Extracellular Matrix Signals

LEE KUI SOON

Cross-Talk

LEE KUI SOON

Apoptosis

LEE KUI SOON

Apoptosis Signals

LEE KUI SOON

 Summary
• Inductive tissue interaction involves inducer and responding
tissues

• The ability to respond ti inductive signals depends upon the

competence of the responding cells

• Reciprocal induction occurs when the two interacting tissues are

both inducers and are competent to respond to each other’s
signals

• Cascades of inductive events are responsible for organ formation

• Regionally specific inductionscan generate different structures

from the same tissue
 Summary
• The ability to respond to inducers is determined by the genetics
state of the responding tissue

• Juxtacrine interactions are inductions that occurs between the cells

membranes of adjacent cells or between a cell membrane and an
extracellular matrix secreted by another cell

• Paracrine interactions occur when a cell or tissue secretes protein

that induce changes in neighboring cells

• Competent cells respond to paracrine factors through signal

transduction pathways. Competence is the ability to bind and to
respond to the inducers and it is often the results of a prior
induction
 Summary
• Signal transduction pathways begin with the paracrine or
juxtacrine factor causing a conformational change in its cell
membrane receptor. The new shape results in enzymatic activity in
the cytoplasmic domains of the receptor protein. This allows the
receptor to phosphorylate other cytoplasmic proteins, thereby
activating a formant kinase activity. Eventually, transcription factor
(or a set of factors) is activated that activates specific gene activity

• Programme cell death is one possible response to inductive stimuli.

Apoptosis is a critical part of life

• There is a cross-talk between signal transduction pathways, which

allows the cell to respond to multiple inputs simultaneously.
THE END