CELL-CELL COMMUNICATION IN DEVELOPMENT

MUSLIMA P. LIWALUG

“The phenomenon of life itself negates the boundaries that customarily divide our

disciplines and fields.”

Hans Jonas (1996)

Cells develop in the context of their environment, including:o their immediate cellular neighborhoodo their tissue identityo their position in the body

Developing cells receive signals from each other of these location, and they, in turn, signal the cells around them.

CONCEPT

COMPONENTS OF SIGNAL/RESPONSE SYSTEM MUST INCLUDE

a signal a receptor to that signal a mechanism to translate and or transport the signal

a mechanism to translate the signal to a stimulation (or repression) of gene expression

CELL-CELL COMMUNICATI

ONOVERVIEW

KNOWLEDGE REQUIRED:

Induction and Competence

Paracrine Factors: The Inducer Molecule

Signal Transduction Cascades: The Response to Inducers

Cell Death Pathways

Juxtacrine Signaling

Cross-Talk Between Pathways

Maintenance of the Differentiated State

INDUCTION & COMPETENCE

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

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; the target tissue

NOTE: The target tissue must be capable of responding equal

Competence – the ability of a cell or tissue to respond to a specific inductive signal

INDUCTION – VERTEBRAE EYE DEVELOPMENT

Lens placode (tissue thickening) – induce head ectoderm by close contact with neural (brain) tissue

The developing lens then includes brain to form the optic cup.

INDUCTION AND COMPETENCE

INDUCTION AND COMPETENCE

INDUCERS

are molecular components

For example optic vesicle inducers:o BMP4 (bone morphogenic protein 4)

- induces Sox2 and Sox3 transcription factorso FgF8 (fibroblast growth factor 8)

- induces L-Maf Transcription Factor

COMPETENCE FACTORCompetence• 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 the other regions of the surface ectoderm.

Pax6 is a competence factor for lens induction.

STEPWISE INDUCTION

Inducer

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)

STEPWISE INDUCTION

RECIPROCAL INDUCTION

MOUSE LENS – RECIPROCAL INDUCTION

Day 9 Mid-Day 9 Mid-Day 10 Mid-Day

11 Day 13

INDUCTIVE INTERACTIONS

Interactions between epithelial and mesenchyme:• mesenchyme plays an instructive role (as the inducing

tissue)• initiates gene activity in epithelial cells

INSTRUCTIVE AND PERMISSIVE

INTERACTIONSINSTRUCTIVE:

A signal from the inducing cell is necessary for initiating new gene expression in the responding cell.

For example, optic vesicle placed under 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 AND PERMISSIVE

INTERACTIONSGeneral 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.

INSTRUCTIVE AND PERMISSIVE

INTERACTIONS INSTRUCTIVE

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

PERMISSIVE

- the responding tissue has already been specified; needs only an environment that allows the expression of those traits.

- permissive interactions tend to regulate the degree of expression of the remaining developmental potential of the cell.

EPITHELIA & MESENCHYME

Epithelia

- sheets or tubes of connected cells

- originate from any cell layer

Mesenchyme

- loosely packed, unconnected

- derived from mesoderm or neural crest

ALL ORGANS CONSIST OF AN EPITHELIUM AND AN ASSOCIATED MESENCHYME

MESENCHYMAL-EPITHELIAL

INTERACTIONS

o many inductions involve interactions between epithelia and mesenchyme

o mesenchyme initiates gene activity in epithelial cells

SOME EPITHELIAL-MESENCHYMAL INTERACTIONS

ORGAN EPITHELIAL COMPONENT MESENCHYMAL COMPONENT

Cutaneous Structures(hair, feather, sweat glans,

mammary glands)

Epidermis(ectoderm)

Dermis(mesoderm)

Limb Epidermis(ectoderm)

Mesenchyme(mesoderm)

Gut organs(liver, pancreas, salivary

glands)

Epidermis(endoderm)

Mesenchyme(mesoderm)

Pharyngeal and Respiratory associated

organs(lungs, thymus, thyroid)

Epithelium(endoderm)

Mesenchyme(mesoderm)

Kidney Ureteric bud epithelium(mesoderm)

Mesenchyme(mesoderm)

Tooth Jaw epithelium(ectoderm)

Mesenchyme(Neural Crest)

SKIN EPITHELIUM & MESENCHYME

Epithelial Derivatives:• Hair• Scales• Feathers• Mammary

glands• Sweat

glands

Derivative type depends on restriction by region and genetics

REGIONAL SPECIFICITYREGIONAL SPECIFICITY - source of the mesenchyme (inducing tissue) determines the structure of the epithelial derivative.

GENETIC SPECIFICITY OF INDCUTION

Genetic specificity – epithelial response is limited to genomic capability

Mesenchyme induces epithelial structures…

…but can only induce what the epithelium is genetically able to produce.

PARACRINE FACTORS:

A TYPE OF INDUCER MOLECULE

Intracellular and intercellular signals.

SIGNAL TRANSDUCTION OR SIGNAL TRANSDUCTION CASCADES

o Response to signals at molecular levelo Signaling pathways gone bad – proto-oncogenes

INDUCING SIGNALS

INDUCING SIGNALS

Self-generated  

Circulating signal

PARACRINE FACTORS

Signaling molecules (proteins) produced by one cell (tissue) and distributed via diffusion to a localized area; often act as inducers.

PARACRINE FACTOR FAMILIES

Fibroblast growth factor (FGF)

Hedgehog family

Wingless family (Wnt)

TGF-βsuperfamily (TGF = transforming growth factor)• TGF-βfamily• Activin family• Bone morphogenic proteins (BMPs)• Vg1 family

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

SIGNAL TRANSDUCTION

CASCADEomost intercellular and intracellular signals are part of larger sets of pathways signal transduction cascades

o activated products or intermediates trigger other pathways

e.g. receptor tyrosine kinase (RTK)

(kinase = enzyme that phosphorylates a protein)

SIGNAL TRANSDUCTION

Receptor Tyrosine Kinase (RTK)

RTK PATHWAY - GENERIC

JAK-STAT PATHWAYJAK (Janus kinase)

- non-receptor tyrosine kinase

STAT (Signal Transducers and Activators of Transcription)- transcription factor

Pathway activators: o prolactin, cytokines, growth hormonesocell proliferationodifferentiationoapoptosis

NOTE: STATs can be activated independently of JAKs• RTK; e.g. EGF receptor• non-receptor tyrosine

kinases; e.g. c-src

JAK-STAT PATHWAY

HEDGEHOG PATHWAY - GENERIC

WNT PATHWAYAPC - adenomatosis polyposis coli (tumor suppressor)

- targets -catenin for degradation

GSK-3 - Glycogen synthase kinase 3

- prevents -catenin dissociation from APC

Wnt binds to Frizzled receptor family

- activates Disheveled

- Disheveled blocks GSK-3

- beta-catenin released from APC

- enters nucleus

- associates with LEF/TCF TFs

WNT PATHWAYS

SMAD PATHWAY

PROTO-ONCOGENES

JUXTACRINE SIGNALING OR EXTRACELLULAR MATRIX SIGNALING

JUXTACRINE SIGNALING

Proteins from the inducing cell interact with receptors from adjacent responding cells without diffusing from the cell producing them

NOTCH PATHWAY1. Delta binds Notch

2. Binding activates proteolytic cleavage of Notch inner portion

3. Proteolytic fragment moves to nucleus

• Displaces repressor• Recruits p300 HAT• Activates transcription

EXTRACELLULAR MATRIX SIGNALS

EMC - 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)

CROSS-TALK

CROSS-TALK

CROSS-TALKSignal 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

CELL DEATH PATHWAYS

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

APOPTOSIS SIGNALSParacrine –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)

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

MAINTAINING DIFFERENTIATION

How to ensure that a tissue remains stable.

MAINTAINING DIFFERENTIATION - 1

1. Activating signal initiates production of a transcription factor which stimulates transcription of its own gene.

MAINTAINING DIFFERENTIATION - 2

2) Synthesized proteins act to stabilize chromatin to keep gene accessible.

MAINTAINING DIFFERENTIATION - 3

3) 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.

MAINTAINING DIFFERENTIATION - 4

4) Paracrine loop - interaction with neighboring cells such that each stimulates differentiation of the other.

DEVELOPMENTAL BIOLOGY EIGHT EDITION

REFERENCE

SCOTT F . G I LBERT

THE END.

SUMMARYCell-Cell Communication

SUMMARY1. Inductive interactions involve inducing and responding tissues.

2. The ability to respond to inductive signals depends upon the competence of the responding cells.

3. Reciprocal induction occurs when the two interacting tissues are both inducers and are competent to respond each other’s signals.

4. Cascades of inductive events are responsible for organ formation.

5. Regionally specific inductions can generate different structures from the same responding tissue.

6. The specific response to an inducer is determined by the genome of the responding tissue.

SUMMARY7. Paracrine interactions occur when a cell or tissue secretes

proteins that induce changes in neighboring cells. Juxtacrine interactions are inductive interactions that take place between the cell membranes of adjacent cells or between a cell membrane and an extracellular matrix secreted by another cell.

8. Paracrine factors are proteins secreted by inducing cells. These factors bind to cell membrane receptors in competent responding cells.

9. 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 result of a prior induction.

SUMMARY10. Signal transduction pathways begin with a paracrine or juxtacrine

factor causing a conformational change in its cell membrane receptor. The new shapes results in enzymatic activity in the cytoplasmic domain of the receptor protein. This activity allows the receptor to phosphorylate other cytoplasmic proteins. Eventually, a cascade of such reactions activates a transcription factor (or set of factors) that activates or represses specific gene activity.

11. Programmed cell death is one possible response to inductive stimuli. Apoptosis is a critical part of life.

12. Gap junctions allow ions and small molecules to move between cells and facilitate coordinated action of coupled cells.

SUMMARY13. There is cross-talk between signal transduction pathways,

which allows the cell to respond to multiple inputs simultaneously.

14. The maintenance of the differentiated state can be accomplished by positive feedback loops involving transcription factors, autocrine factors, or paracrine factors.