Cell-Cell Communication in Development

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1 Biology Developmental Biology Cell-Cell Communication in Development October 2, 2007

2 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

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

4 Induction and Competence

Competence Factors Competence the ability of a cell or tissue to respond to a specific inductive signal - not a passive state - actively acquired (and can also be transient) - during lens induction

5 Competence Factors Competence the ability of a cell or tissue to respond to a specific inductive signal - not a passive state - actively acquired (and can also be transient) - during lens induction Pax6 is expressed in the headpax6 ectoderm, but not in other regions of surface ectoderm Pax6 = is a competence factor for lens induction Competence factors (inducers) Pax6 - often multiple inducers for a given tissue; e.g. for lens: -1 st inducer - pharyngeal endoderm & heart-forming mesoderm -2 nd inducer anterior neural plate (including Pax6 synthesis) - optic vesicle inducers: BMP4 (bone morphogenic protein 4) Fgf8 (fibroblast growth factor 8)

6 Lens Induction in Amphibians

7 Lens Induction - 2

8 Mouse Lens Induction

9 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; need 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.

10 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

12 Skin Epithelium & Mesenchyme epithelial derivatives: - hair - mammary glands - scales - sweat glands - feathers Epithelium inductive signals Mesenchyme

13 Regional Specificity of Induction The source of the mesenchyme (the inducing tissue) determines the structure of the epithelial derivative.

14 Genetic Specificity of Induction Mesenchyme induces epithelial structures - - but can only induce what the epithelium is genetically able to produce

15 Inducing Signals Also: endocrine signals autocrine (self-generated) signals

16 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

17 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 receptor spans membrane ligand binding = conformational change autophosphorylation intracellular signal

Ras-GDP Ras-GTP (8. GAP recycles Ras) 9. active Ras activates Raf (protein kinase C) 10.

18 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

19 RTK Pathway Mitf Stem cell factor (a paracrine factor) stimulates genes needed for melanocyte production.

20 STAT Pathway Casein Gene

21 Hedgehog Pathway

22 canonical Wnt pathway Wnt Pathways

23 SMAD Pathway

24 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.

25 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.

26 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)

in the intersticies between the cells - cell adhesion, migration, formation

27 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)

28 Maintaining Differentiation - 1 1) Activated transcription factor binds to its own enhancer.

29 Maintaining Differentiation - 2 2) Synthesized proteins act to stabilize chromatin to keep gene accessible.

30 Maintaining Differentiation - 3 3) Maintain diffferentiation through autocrine signaling: same cell makes both the signaling molecule and receptor.

31 Maintaining Differentiation - 4 4) Interaction with neighboring cells such that one stimulates differentiation of the other.

32 Community Effect Community effect - The exchange of signals among equivalent cells stabilizes the same determined state for all of them.

Cell Cell Communication in Development

Biology 4361 Developmental Biology Cell Cell Communication in Development June 25, 2008 Cell Cell Communication Concepts Cells in developing organisms develop in the context of their environment, including