Cell Cell Communication in Development

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1 Biology 4361 Developmental Biology Cell Cell Communication in Development June 25, 2008

2 Cell Cell Communication Concepts Cells in developing organisms develop in the context of their environment, including their immediate cellular neighborhood, their tissue identity, and their position in the body. Developing cells receive signals from each of these locations, and they, in turn, signal the cells around them. The components of this signal/response system must include: 1) a signal 2) a receptor for that signal 3) a mechanism to translate and/or transport the signal (or signal product) 4) a mechanism to translate the signal to a stimulation (or repression) of gene expression

3 Cell Cell Communication 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 Juxtacrine signaling / extracellular matrix signaling Cell death pathways Cross talk Maintenance of the differentiated state How to ensure that a tissue remains stable

4 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 target tissue must be capable of responding = Competence the ability of a cell or tissue to respond to a specific inductive signal.

5 Induction Vertebrate Eye Development Lens placode (tissue thickening) induced in head ectoderm by close contact with neural (brain) tissue The developing lens then induces brain to form the optic cup

6 Induction and Competence

7 Competence Factors Competence the 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 Pax6 Pax6 is a competence factor for lens induction

8 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

9 Inducers Stepwise Induction Often multiple inducer tissues operate on a structure; e.g. for frog lens: 1 st inducer pharyngeal endoderm & heart forming mesoderm 2 nd inducer anterior neural plate (including signal for ectoderm Pax6 synthesis)

10 Reciprocal Induction A B C D

11 Mouse Lens Reciprocal Induction

12 Inductive Interactions Many inductions involve interactions between epithelia and mesenchyme. Mesenchyme plays an instructive role (as the inducing tissue) initiates gene activity in epithelial cells

13 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 the inducing cell, the responding cell is not capable of differentiating (in that particular way). instructive interactions 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; needs 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.

Epithelia and Mesenchyme Epithelia sheets or tubes of connected

unconnected cells derived from mesoderm or neural crest All organs

Mesenchymal epithelial interactions: Many inductions involve

14 Epithelia and Mesenchyme Epithelia sheets or tubes of connected cells originate 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. Mesenchymal epithelial interactions: Many inductions involve interactions between epithelia and mesenchyme. Mesenchyme initiates gene activity in epithelial cells

16 Skin Epithelium & Mesenchyme Epithelium inductive signals Mesenchyme epithelial derivatives: hair mammary glands scales sweat glands feathers derivative type depends on restrictions by region and genetics

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

18 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

19 Cell Cell Communication Overview Induction and competence How do cells and tissues know how to develop? Paracrine factors inducer molecules Intracellular signals Signal transduction / signal transduction cascades Responses to inter and intracellular signaling Signaling pathways gone bad Proto oncogenes Juxtacrine signaling/extracellular matrix signaling Cell death pathways Cross talk Maintenance of the differentiated state How to ensure that a tissue remains stable

20 Concepts Cell Cell Communication Cells in developing organisms develop in the context of their environment, including their immediate cellular neighborhood, their tissue identity, and their position in the body. Developing cells receive signals from each of these locations, and they, in turn, signal the cells around them. The components of this signal/response system must include: 1) a signal 2) a receptor for that signal 3) a mechanism to translate and/or transport the signal (or signal product) 4) a mechanism to translate the signal to a stimulation (or repression) of gene expression

21 Inducing Signals Also: autocrine (self generated) signals endocrine signals

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

22 Paracrine Factors 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 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

23 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 cascades most intercellular and intracellular signals are part of larger sets of pathways activated products or intermediates trigger other pathways e.g. receptor tyrosine kinase (RTK) (kinase = enzyme that phosphorylates a protein)

24 Signal Transduction; e.g. RTK Receptor Tyrosine Kinase (RTK) receptor spans membrane ligand binding = conformational change = hormone or paracrine factor autophosphorylation intracellular signal

RTK Pathway Generic 1. Ligand binding 2. RTK dimerized 3. RTK autophosphorylation 4. Adaptor protein binding 5. GNRP binding 6. GNRP activates Ras (G protein) 7. Ras GDP Ras GTP (8.

25 RTK Pathway Generic 1. Ligand binding 2. RTK dimerized 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

26 STAT Pathway Casein Gene

27 Hedgehog Pathway Generic Drosophila Mammalian Ci homolog Gli zinc finger TF

28 canonical Wnt pathway Wnt Pathways

29 TGF β superfamily ligands TGF βs BMPs Activins Dpp Inhibin Nodal Vg1 etc. SMAD Pathway C. elegans Sma Drosophila Mad Smad R Smad co Smad

30 Proto Oncogenes Proto oncogenes (onco = cancer) when inappropriately activated cause tumor formation Proto oncogenes are active during development repressed/silenced in adult Mutations (e.g. constitutive activation) = oncogene many cancers have mutated proto oncogenes e.g. mutated Ras found in 20 30% of all tumors

31 Cell Cell Communication Overview Induction and competence How do cells and tissues know how to develop? Paracrine factors inducer molecules Intracellular signals Signal transduction cascades Responses to inter and intracellular signaling Juxtacrine signaling/extracellular matrix signaling Cross talk Cell death pathways Maintenance of the differentiated state How to ensure that a tissue remains stable

Notch Pathway Juxtacrine signaling: Proteins from the

responding cells without diffusing from the cell

etc. Delta binds Notch (Serrate) (Jagged) Binding

32 Notch Pathway Juxtacrine signaling: Proteins from the inducing cell interact with receptors from adjacent responding cells without diffusing from the cell producing them. e.g. Notch/Delta, Ephrin/EphR, EGF/EGFR, IL 15/IL 15Rα, etc. Delta binds Notch (Serrate) (Jagged) Binding activates proteolytic cleavage of Notch inner portion Proteolytic fragment moves to nucleus displaces repressor recruits p300 HAT activates transcription

material in the intersticies between the cells cell adhesion, migration,

33 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)

34 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

35 Cell Cell Communication Overview Induction and competence How do cells and tissues know how to develop? Paracrine factors inducer molecules Intracellular signals Signal transduction cascades Responses to inter and intracellular signaling Juxtacrine signaling/extracellular matrix signaling Cross talk Cell death pathways Maintenance of the differentiated state How to ensure that a tissue remains stable

Apoptosis Apoptosis programmed cell death Developmental: embryonic neural growth embryonic brain produces 3X neurons found at birth hand and

36 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

Apoptosis Signals Paracrine e.g. BMP4 (connective tissues, frog ectoderm, tooth primordia), JAK STAT, Hedgehog Pre programming: some cells will die unless rescued ; e.

37 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.

38 Maintaining Differentiation 1 1) Activating signal initiates production of a transcription factor which stimulates transcription of its own gene.

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

40 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.

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

Cell-Cell Communication in Development

Biology 4361 - Developmental Biology Cell-Cell Communication in Development October 2, 2007 Cell-Cell Communication - Topics Induction and competence Paracrine factors inducer molecules Signal transduction