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Cell to Cell Communication in Development
Cell-cell communication is essential for development, involving inductive interactions between tissues that influence cell behavior and gene expression. Competence determines a responding tissue's ability to react to inductive signals, which can lead to reciprocal induction and organ formation. Specific responses to inducers are guided by genetic capabilities, and the process is mediated through paracrine and juxtacrine signaling pathways.
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Cell to Cell Communication in Development
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- 3. “The phenomenon oflife itself negates the boundaries that customarily divide our disciplines and fields.” Hans Jonas (1996)
- 4. Cells develop inthe context of their environment, including: o their immediate cellular neighborhood o their tissue identity o their position in the body Developing cells receive signals from each other of these location, and they, in turn, signal the cells around them.
- 5. COMPONENTS OF SIGNAL/RESPONSE SYSTEMMUST 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
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- 7. Induction and Competence ParacrineFactors: The Inducer Molecule Signal Transduction Cascades: The Response to Inducers Cell Death Pathways Juxtacrine Signaling Cross-Talk Between Pathways Maintenance of the Differentiated State
- 8. INDUCTION & COMPETENCE How docells and tissues “know” how to develop?
- 9. INDUCTION AND COMPETENCE Development dependson 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
- 11. Lens placode (tissuethickening) – induce head ectoderm by close contact with neural (brain) tissue The developing lens then includes brain to form the optic cup.
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- 14. INDUCERS are molecular components Forexample optic vesicle inducers: o BMP4 (bone morphogenic protein 4) - induces Sox2 and Sox3 transcription factors o FgF8 (fibroblast growth factor 8) - induces L-Maf Transcription Factor
- 15. Competence • ability ofa 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.
- 16. STEPWISE INDUCTION Inducer Often multipleinducer 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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- 19. MOUSE LENS – RECIPROCALINDUCTION Day 9 Mid-Day 9 Mid-Day 10 Mid-Day 11 Day 13
- 20. INDUCTIVE INTERACTIONS Interactions between epithelialand mesenchyme: • mesenchyme plays an instructive role (as the inducing tissue) • initiates gene activity in epithelial cells
- 21. INSTRUCTIVE AND PERMISSIVE INTERACTIONS INSTRUCTIVE: Asignal 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.
- 22. INSTRUCTIVE AND PERMISSIVE INTERACTIONS GeneralPrinciples 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.
- 23. 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.
- 24. EPITHELIA & MESENCHYME Epithelia - sheetsor 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
- 25. MESENCHYMAL-EPITHELIAL INTERACTIONS o many inductionsinvolve interactions between epithelia and mesenchyme o mesenchyme initiates gene activity in epithelial cells
- 26. SOME EPITHELIAL- MESENCHYMAL INTERACTIONS ORGANEPITHELIAL 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)
- 27. SKIN EPITHELIUM & MESENCHYME Epithelial Derivatives: •Hair • Scales • Feathers • Mammary glands • Sweat glands Derivative type depends on restriction by region and genetics
- 28. REGIONAL SPECIFICITY REGIONAL SPECIFICITY- source of the mesenchyme (inducing tissue) determines the structure of the epithelial derivative.
- 29. GENETIC SPECIFICITY OF INDCUTION Geneticspecificity – epithelial response is limited to genomic capability Mesenchyme induces epithelial structures… …but can only induce what the epithelium is genetically able to produce.
- 30. PARACRINE FACTORS: A TYPEOF INDUCER MOLECULE Intracellular and intercellular signals.
- 31. SIGNAL TRANSDUCTION OR SIGNALTRANSDUCTION CASCADES o Response to signals at molecular level o Signaling pathways gone bad – proto-oncogenes
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- 34. PARACRINE FACTORS Signaling molecules(proteins) produced by one cell (tissue) and distributed via diffusion to a localized area; often act as inducers.
- 35. PARACRINE FACTOR FAMILIES Fibroblast growthfactor (FGF) Hedgehog family Wingless family (Wnt) TGF-βsuperfamily (TGF = transforming growth factor) • TGF-βfamily • Activin family • Bone morphogenic proteins (BMPs) • Vg1 family
- 36. SIGNAL TRANSDUCTION Extracellular signalsare received at the membrane and then transduced to the cytoplasm at the cell membrane - external signal is transmitted into the interior of the cell
- 37. SIGNAL TRANSDUCTION CASCADE omost intercellularand 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)
- 38. SIGNAL TRANSDUCTION Receptor TyrosineKinase (RTK)
- 39. RTK PATHWAY -GENERIC
- 40. JAK-STAT PATHWAY JAK (Januskinase) - non-receptor tyrosine kinase STAT (Signal Transducers and Activators of Transcription) - transcription factor Pathway activators: o prolactin, cytokines, growth hormones ocell proliferation odifferentiation oapoptosis 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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- 43. WNT PATHWAY APC -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
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- 48. JUXTACRINE SIGNALING Proteins fromthe inducing cell interact with receptors from adjacent responding cells without diffusing from the cell producing them
- 49. NOTCH PATHWAY 1. Deltabinds Notch 2. Binding activates proteolytic cleavage of Notch inner portion 3. Proteolytic fragment moves to nucleus • Displaces repressor • Recruits p300 HAT • Activates transcription
- 50. 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)
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- 53. CROSS-TALK Signal transduction isoften 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
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- 55. APOPTOSIS - programmed celldeath 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
- 56. APOPTOSIS SIGNALS 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) Mechanism – caspases (proteases) – cause autodigestion of the cell.
- 57. MAINTAINING DIFFERENTIATION How to ensurethat a tissue remains stable.
- 58. MAINTAINING DIFFERENTIATION - 1 1.Activating signal initiates production of a transcription factor which stimulates transcription of its own gene.
- 59. MAINTAINING DIFFERENTIATION - 2 2)Synthesized proteins act to stabilize chromatin to keep gene accessible.
- 60. 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.
- 61. MAINTAINING DIFFERENTIATION - 4 4)Paracrine loop - interaction with neighboring cells such that each stimulates differentiation of the other.
- 62. EIGHT EDITION REFERENCE SC OT T F. GI L B E RT
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- 65. SUMMARY 1. Inductive interactionsinvolve 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.
- 66. SUMMARY 7. Paracrine interactionsoccur 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.
- 67. SUMMARY 10. Signal transductionpathways 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.
- 68. SUMMARY 13. There iscross-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.