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Biology 4361 - Developmental Biology
Cell-Cell Communication in
Development
October 9, 2007
General Questions:
1. How do cells differentiate? [Differentiation]
2. How are cell organized into tissues and organs? [Morphogenesis]
3. How do cells know when to stop dividing? [Growth]
4. How is gametogenesis accomplished? [Reproduction]
5. How do changes in development create new body forms? [Evolution]
6. How is development of an organism integrated into the larger context
of its habitat? [Environmental integration]
Cell–Cell Communication - Topics
Induction and competence
Paracrine factors – inducer molecules
Signal transduction cascades
Cell death pathways
Juxtacrine signaling
Cross-talk between pathways
Maintenance of the differentiated state
Induction and Competence
Development depends on the precise arrangement of tissues and cells.
- organ construction is precisely coordinated in time and space
- arrangements of cells and tissues change over time
Induction – interaction at close range between two or more cells or tissues with
different histories and properties.
Inducer – tissue that produces a signal that changes cellular behavior.
Responder – tissue being induced.
Note – the target tissue must be capable of responding = competence
Competence – the ability of a cell or tissue to respond to a specific inductive signal.
Induction - Vertebrate Eye Development
Lens placode (tissue thickening) induced in head ectoderm
by close contact with neural (brain) tissue
The developing lens induces brain to form the optic cup
(Reciprocal Induction)
Induction and Competence
Competence Factors
Competence – the ability of a cell or tissue to respond to a
specific inductive signal
- actively acquired (and can also be transient)
During lens induction Pax6 is expressed in the
head ectoderm, but not in other regions of
surface ectoderm
Pax6
Pax6
Pax6 is a competence factor for lens induction
Stepwise Induction
Inducers
Often multiple inducer tissues operate on a structure; e.g. for frog lens:
- 1st inducer - pharyngeal endoderm & heart-forming mesoderm
- 2nd inducer - anterior neural plate (including signal for ectoderm
Pax6 synthesis)
Inducers are molecular components; e.g. optic vesicle inducers:
- BMP4 (bone morphogenic protein 4)
- induces Sox2 and Sox3 transcription factors
- Fgf8 (fibroblast growth factor 8)
- induces L-Maf transcription factor
Lens Induction
Reciprocal Induction
A
B
C
D
Mouse Lens – Reciprocal Induction
Instructive and Permissive Interactions
Instructive: a signal from the inducing cell is necessary for initiating new
gene expression in the responding cell
- e.g. optic vesicle placed under a new region of head ectoderm
- without inducing cell, the responding cell is not capable of differentiating
(in that particular way).
- tend to restrict the cell’s developmental options
General principles of 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.
Permissive: the responding tissue has already been specified; needs only an
environment that allows the expression of those traits.
- tend to regulate the degree of expression of the remaining
developmental potential of the cell.
Induction Between
Epithelia and Mesenchyme
Epithelia – sheets or tubes of connected cells
- originates from any cell layer
Mesenchyme – loosely packed, unconnected cells
- derived from mesoderm or neural crest
All organs consist of an epithelium and an associated mesenchyme.
Many inductive events involve interactions between epithelia and mesenchyme.
General properties of epithelial-mesenchymal inductions:
Mesenchyme plays an instructive role – initiating gene activity in
responding epithelial cells
Regional specificity of induction
Genetic specificity of induction
Skin Epithelium & Mesenchyme
epithelial derivatives:
- hair
- mammary glands
- scales
- sweat glands
- feathers
Epithelium
inductive
signals
Mesenchyme
Regional Specificity of Induction
The source of the mesenchyme (the inducing tissue) determines
the structure of the epithelial derivative.
Genetic Specificity of Induction
Mesenchyme induces
epithelial structures - but can only induce
what the epithelium is
genetically able to produce
Inducing Signals
Also:
endocrine signals
autocrine (self-generated) signals
Paracrine Factor Families
Fibroblast growth factor (FGF)
Hedgehog family
Wingless family (Wnt)
TGF-β superfamily (TGF = transforming growth factor)
- TGF-β family
- Activin family
- Bone morphogenic proteins (BMPs)
- Vg1 family
Signal Transduction
Inducing signals are transduced at the cell membrane; i.e. an external signal
(a paracrine factor or hormone) is transmitted into the interior of the cell
e.g. receptor tyrosine kinase (RTK)
(kinase = protein phosphorylating enzyme)
= hormone or
paracrine factor
ligand binding =
receptor
spans
membrane
conformational change
autophosphorylation
intracellular
signal
RTK Pathway
1. ligand binding
2. RTK dimerized
3. RTK phosphorylation
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)
10. Raf phosphorylates MEK
11. MEK phosphorylates
ERK (a kinase)
12. ERK phosphorylates
transcription factors
13. transcription activates
RTK Pathway – Mitf
Stem cell factor (a paracrine factor) stimulates genes needed for melanocyte production.
STAT Pathway – Casein Gene
Hedgehog Pathway
Wnt Pathways
canonical Wnt pathway
SMAD Pathway
Apoptosis
Apoptosis – programmed cell death
e.g. - embryonic neural growth
- embryonic brain produces
3X neurons found at birth
- hand and foot
- webbing between digits
- teeth
- middle ear space
- vaginal opening
- male mammary tissue
- frog tails (at metamorphosis)
Apoptosis Signals
BMP4 – mammalian connective tissues, frog ectoderm, tooth primordia
Pre-programming: some cells (e.g. mammalian RBCs) will die unless
“rescued” by erythropoietin.
- erythropoietin – hormone ligand that works thought the JAK-STAT pathway
Caspase(s) – proteases – cause autodigestion of the cell.
Juxtacrine Signaling
Proteins from the inducing cell interact with receptors from adjacent
responding cells without diffusing from the cell producing them.
e.g. Notch:
(or Serrate
or Jagged)
Extracellular Matrix Signals
ECM – macromolecules secreted by cells into their immediate environment
- macromolecules form a region of non-cellular material in the intersticies
between the cells
- cell adhesion, migration, formation of epithelial sheets and tubes
- collagen, proteoglycans (fibronectin, laminin)
Maintaining Differentiation - 1
1) Activated transcription factor binds to its own enhancer.
Maintaining Differentiation - 2
2) Synthesized proteins act to stabilize chromatin to keep gene accessible.
Maintaining Differentiation - 3
3) Maintain diffferentiation through autocrine signaling: same cell makes
both the signaling molecule and receptor.
Maintaining Differentiation - 4
4) Interaction with neighboring cells such that one stimulates
differentiation of the other.
Community Effect
Community effect The exchange of signals among equivalent cells
stabilizes the same determined state for all of them.