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Cell-Cell Communication in Development Biology 4361 - Developmental Biology June 23, 2009

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Page 1: Cell-Cell Communication in Developmentpschoff/documents/Cell-Cell... · Cell-Cell Communication in Development ... produced by one cell (tissue) ... - external signal is transmitted

Cell-Cell Communication in

Development

Biology 4361 - Developmental Biology

June 23, 2009

Page 2: Cell-Cell Communication in Developmentpschoff/documents/Cell-Cell... · Cell-Cell Communication in Development ... produced by one cell (tissue) ... - external signal is transmitted

Cell-Cell CommunicationConcepts

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

The components of this signal/response system must include:

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Cell-Cell Communication

Juxtacrine signaling / extracellular matrix signaling

Overview

Induction and competence

- how do cells and tissues “know” how to develop?

Paracrine factors – a type of inducer molecule

- inter- and intracellular signals

Signal transduction / signal transduction cascades

- response to signals at the molecular level

Maintenance of the differentiated state

- how to ensure that a tissue remains stable

Cell death pathways

Cross-talk

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Induction and Competence

Competence – the ability of a cell or tissue to respond to a

specific inductive signal.

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; the target tissue

Note – the target tissue must be capable of responding =

Page 5: Cell-Cell Communication in Developmentpschoff/documents/Cell-Cell... · Cell-Cell Communication in Development ... produced by one cell (tissue) ... - external signal is transmitted

Induction - Vertebrate Eye Development

MRC Human Embryo Bank / Wellcome Photo Library

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Induction - Vertebrate Eye Development

The developing lens then induces brain to

form the optic cup

Lens placode (tissue thickening) induced in head

ectoderm by close contact with neural (brain) tissue

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Induction and Competence

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Pax6

Pax6

Competence Factors

Competence - 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 is a competence factor for lens induction

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Inducers

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

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Stepwise InductionInducers

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)

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Reciprocal Induction

A

B

C

D

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Mouse Lens – Reciprocal Induction

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Inductive Interactions

Interactions between epithelia and mesenchyme:

- mesenchyme plays an instructive role (as the inducing tissue)

- initiates gene activity in epithelial cells

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Instructive and Permissive Interactions

A signal from the inducing cell is necessary for initiating new

gene expression in the responding cell

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.

e.g. optic vesicle placed under a new region of head ectoderm

-without the inducing cell, the responding cell is not capable

of differentiating (in that particular way).

Instructive interactions restrict the cell’s developmental options

Instructive:

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Instructive and Permissive Interactions

Permissive:

Permissive interactions tend to regulate the degree of expression

of the remaining developmental potential of the cell.

The responding tissue has already been specified; needs only an

environment that allows the expression of those traits.

A signal from the inducing cell is necessary for initiating new

gene expression in the responding cell

Instructive:

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Epithelia and Mesenchyme

Many inductions involve interactions between

epithelia and mesenchyme.

Mesenchymal-epithelial interactions:

Mesenchyme initiates gene activity in epithelial cells

Mesenchyme – loosely packed, unconnected

- derived from mesoderm or neural crest

All organs consist of an epithelium

and an associated mesenchyme.

Epithelia – sheets or tubes of connected cells

- originate from any cell layer

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Skin Epithelium & Mesenchyme

Epithelium

Mesenchyme

inductive

signals

epithelial derivatives:

- feathers

- hair - mammary glands- scales - sweat glands

derivative type depends

on restrictions by region

and genetics

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Regional Specificity of Induction

Regional Specificity - source of the mesenchyme (inducing tissue)

determines the structure of the epithelial derivative.

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Genetic Specificity of Induction

Mesenchyme induces

epithelial structures…

…but can only induce

what the epithelium is

genetically able to produce

Genetic specificity – epithelial response is limited to genomic capability

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Cell-Cell Communication

Juxtacrine signaling / extracellular matrix signaling

Overview

Induction and competence

- how do cells and tissues “know” how to develop?

Paracrine factors – a type of inducer molecule

- inter- and intracellular signals

Maintenance of the differentiated state

- how to ensure that a tissue remains stable

Signal transduction / signal transduction cascades

- response to signals at the molecular level

- signaling pathways gone bad – proto-oncogenes

Cell death pathways

Cross-talk

Page 22: Cell-Cell Communication in Developmentpschoff/documents/Cell-Cell... · Cell-Cell Communication in Development ... produced by one cell (tissue) ... - external signal is transmitted

Cell-Cell CommunicationConcepts

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

The components of this signal/response system must include:

Page 23: Cell-Cell Communication in Developmentpschoff/documents/Cell-Cell... · Cell-Cell Communication in Development ... produced by one cell (tissue) ... - external signal is transmitted

Inducing Signals

Also:

autocrine (self-generated) signals

endocrine signals

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Paracrine Factors

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

Signaling molecules (proteins) produced by one cell (tissue) and

distributed via diffusion to a localized area; often act as inducers.

(Compare “endocrine”, “autocrine”, “juxtracrine” factors)

Paracrine Factor Families

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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 phosphorylates a protein)

- most intercellular and intracellular signals are part of larger

sets of pathways

Signal transduction cascades

- activated products or intermediates trigger other pathways

Page 26: Cell-Cell Communication in Developmentpschoff/documents/Cell-Cell... · Cell-Cell Communication in Development ... produced by one cell (tissue) ... - external signal is transmitted

Signal Transduction; e.g. RTK

= hormone or

paracrine factor

autophosphorylation

intracellular

signal

receptor

spans

membrane

ligand binding =

conformational change

Receptor Tyrosine Kinase (RTK)

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RTK Pathway - Generic

2. RTK dimerized

1. Ligand binding

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

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JAK-STAT PathwayJAK – 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

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Hedgehog Pathway - Generic

Drosophila

Mammalian Ci

homolog - Gli

- zinc finger TF

Page 30: Cell-Cell Communication in Developmentpschoff/documents/Cell-Cell... · Cell-Cell Communication in Development ... produced by one cell (tissue) ... - external signal is transmitted

Wnt PathwayCanonical Wnt pathway

GSK-3 - Glycogen synthase kinase 3

- prevents -catenin dissociation from APC

APC - adenomatosis polyposis coli

(tumor suppressor)

- targets -catenin for degradation

Wnt binds to Frizzled receptor family

- activates Disheveled

- Disheveled blocks GSK-3

- -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

Drosophila Wingless

mouse IntegrationWnt

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Wnt PathwaysPlanar cell polarity pathway

cell morphology, movement, division Ca2+-dependent gene expression

Ca2+ pathway

phosphatase

phospholipase C

- IP3

- diacylglycerol

b. Rac:

GTPase

Jun kinase

a. Rho:

GTPase

Rho-

associated

kinase

tether

(inactive)

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SMAD Pathway

R-Smad

co-Smad

C. elegans Sma

Drosophila MadSmad

TGF-β superfamily ligands

TGF-βs

BMPs

Activins

Dpp

Inhibin

Nodal

Vg1

etc.

Page 33: Cell-Cell Communication in Developmentpschoff/documents/Cell-Cell... · Cell-Cell Communication in Development ... produced by one cell (tissue) ... - external signal is transmitted

Proto-Oncogenes

Proto-oncogenes

(onco = cancer)

e.g. mutated Ras found in

20-30% of all tumors

- many cancers have

mutated proto-oncogenes

Mutations (e.g. constitutive

activation) = oncogene

- active during development

- repressed/silenced in adult

- cause tumor formation

when inappropriately

activated

Page 34: Cell-Cell Communication in Developmentpschoff/documents/Cell-Cell... · Cell-Cell Communication in Development ... produced by one cell (tissue) ... - external signal is transmitted

Cell-Cell Communication

Juxtacrine signaling / extracellular matrix signaling

Overview

Induction and competence

- how do cells and tissues “know” how to develop?

Paracrine factors – a type of inducer molecule

- inter- and intracellular signals

Signal transduction / signal transduction cascades

- response to signals at the molecular level

Maintenance of the differentiated state

- how to ensure that a tissue remains stable

Cell death pathways

Cross-talk

Page 35: Cell-Cell Communication in Developmentpschoff/documents/Cell-Cell... · Cell-Cell Communication in Development ... produced by one cell (tissue) ... - external signal is transmitted

Juxtracrine Signaling

Proteins from the inducing cell interact with

receptors from adjacent responding cells

without diffusing from the cell producing them.

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Notch Pathway

1. Delta binds Notch

(Serrate)

(Jagged)

3. Proteolytic fragment

moves to nucleus

- displaces repressor

- recruits p300 HAT

- activates

transcription

2. Binding activates

proteolytic cleavage

of Notch inner portion

Page 37: Cell-Cell Communication in Developmentpschoff/documents/Cell-Cell... · Cell-Cell Communication in Development ... produced by one cell (tissue) ... - external signal is transmitted

Extracellular Matrix SignalsECM – macromolecules secreted by cells into their immediate environment

- macromolecules form a region of non-cellular material between the cells

- cell adhesion, migration, formation of epithelial sheets and tubes

- collagen, proteoglycans (fibronectin, laminin)

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Cross-Talk

Signal transduction is often not

a linear event; e.g.

- cascades

- multiple signals required

- multiple products required

also:

- inhibitory signals

- promiscuous signals/receptors

Cross-talk provides opportunities

for emergent properties; e.g.

- hypersensitivity

- stability

- bistability

Page 39: Cell-Cell Communication in Developmentpschoff/documents/Cell-Cell... · Cell-Cell Communication in Development ... produced by one cell (tissue) ... - external signal is transmitted

Cell-Cell Communication

Cell death pathways

Juxtacrine signaling / extracellular matrix signaling

Overview

Induction and competence

- how do cells and tissues “know” how to develop?

Paracrine factors – a type of inducer molecule

- inter- and intracellular signals

Signal transduction / signal transduction cascades

- response to signals at the molecular level

Maintenance of the differentiated state

- how to ensure that a tissue remains stable

Cross-talk

Page 40: Cell-Cell Communication in Developmentpschoff/documents/Cell-Cell... · Cell-Cell Communication in Development ... produced by one cell (tissue) ... - external signal is transmitted

Apoptosis

Apoptosis – programmed cell death

Developmental:

- 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)

Adult:

- most cells and tissues

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Apoptosis Signals

Mechanism – caspases (proteases) – cause autodigestion of the cell.

Paracrine – e.g. BMP4 (connective tissues, frog ectoderm, tooth primordia),

JAK-STAT, Hedgehog

Pre-programming: some cells will die unless “rescued”; e.g. mammalian

RBCs rescued by erythropoietin (hormone; activates JAK-STAT)

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Maintaining Differentiation - 1

1) Activating signal initiates production of a transcription factor

which stimulates transcription of its own gene.

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Maintaining Differentiation - 2

2) Synthesized proteins act to stabilize chromatin to keep

gene accessible.

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Maintaining Differentiation – 33) Autocrine signaling: same cell makes signaling molecule

and receptor.

Community effect - the exchange of signals among equivalent

cells stabilizes the same determined state for all of them.

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Maintaining Differentiation – 4

4) Paracrine loop - interaction with neighboring cells such that

each stimulates differentiation of the other.