cell to cell communication in development
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.
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
Induction and Competence
Paracrine Factors: The Inducer Molecule
Signal Transduction Cascades: The Response to Inducers
Cell Death Pathways
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
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
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.
Often multiple inducer tissues operate on a structure; e.g. for frog lens:1st inducer – pharyngeal endoderm & heart-forming
2nd inducer – anterior neural plate (including signal for ectoderm Pax6 synthesis)
MOUSE LENS – RECIPROCAL INDUCTION
Day 9 Mid-Day 9 Mid-Day 10 Mid-Day
11 Day 13
Interactions between epithelial and mesenchyme:• mesenchyme plays an instructive role (as the inducing
tissue)• initiates gene activity in epithelial cells
INSTRUCTIVE AND PERMISSIVE
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
- a signal from the inducing cell is necessary for initiating new gene expression in the responding cell
- 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
- sheets or tubes of connected cells
- originate from any cell layer
- loosely packed, unconnected
- derived from mesoderm or neural crest
ALL ORGANS CONSIST OF AN EPITHELIUM AND AN ASSOCIATED MESENCHYME
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,
Gut organs(liver, pancreas, salivary
Pharyngeal and Respiratory associated
organs(lungs, thymus, thyroid)
Kidney Ureteric bud epithelium(mesoderm)
Tooth Jaw epithelium(ectoderm)
SKIN EPITHELIUM & MESENCHYME
Epithelial Derivatives:• Hair• Scales• Feathers• Mammary
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.
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
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)
Wingless family (Wnt)
TGF-βsuperfamily (TGF = transforming growth factor)• TGF-βfamily• Activin family• Bone morphogenic proteins (BMPs)• Vg1 family
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
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)
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
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
JUXTACRINE SIGNALING OR EXTRACELLULAR MATRIX 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-TALKSignal transduction is often not a linear event
e.g. cascades multiple signals required multiple products required
also: inhibitory signals promiscuous
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.
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
SCOTT F . G I LBERT
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.