Cell-Cell Signaling Inductive Interactions

Induction: proximate interactions Close range interactions Inducer –Tissue doing the inducing –Emits a signal Secreted peptides Cell associated proteins Responder –Tissues/cells that receive the signal –Change as a result of receiving signal –Express receptor to interact with secreted signaling molecule

Induction Competence –The ability of a group of cells to respond to the inducing signal –Essentially means competent cells have receptors and all necessary second messengers necessary to respond appropriately to the signal

Types of Inductive Interactions Instructive interactions –Signals cause a response –Signals are required for the response –A specific response is induced –Ligand-receptor interactions setting off signal cascade Permissive interactions –Signals allow a response –Signals do not designate a specific response –ECM allows differentiation

Examples of Embryonic Inductions Primary inductions –Mesoderm induction –Neural induction Secondary inductions –Lens –Retina –Epidermal (hair, scales, feathers) –Tooth –Many organs

Sequential Inductive Interactions in Eye Formation

Lens induction in amphibians

Sequential Inductive Interactions in Eye Formation Lens & retina formation in rodents

Epithelial-Mesenchymal Interactions Epithelial cells –Cells of epidermal or endodermal origin –have distinct epithelial morphology Mesenchymal cells –Cells of mesodermal origin –Have a distinct mesenchymal morphology

Mesenchymal-Epithelial Interactions Epidermis is competent to differentiate into epidermal structures (follicles). The dermis is the source of inducing signals to specify the type of epidermal structure formed.

Mesenchymal-Epithelial Interactions Epithelial tissue can only respond within the limits of its genetic programming. The age old question - Does a chicken have lips?

Mechanisms of Inductive Signaling Paracrine signaling –Secreted, diffusible signaling molecules Peptide growth factors (PGFs) or peptide inducing factors (PIFs) Not exactly the same as hormones – not secreted into bloodstream but into intercellular space Signaling at a limited distance Juxtacrine signaling –Non-soluble signaling molecules Integral or membrane associated proteins Signaling occurs at point of cell-cell contact

Mechanisms of Inductive Signaling Paracrine Signaling Juxtacrine Signaling

Secreted Signaling Molecules FGF Family Hedgehog Family Wnt Family TGF  Superfamily –TGF  Family –Activin Family –BMP Family EGF Family PDGF Family Retinoids HGF/Scatter Factor Neurotrophins Semaphorins Cytokines

Receptors for Soluble Signaling Molecules Receptor Tyrosine Kinase (RTK) pathway –FGFR, EGFR, PDGFR –Receptor coupled to ras signal transduction cascade Smad pathway –Bipartite Serine/Threonine Kinase Receptors –AcRI/II, TGF  RI/II, BMPRI/IIs –Receptors activate Smad transcription factors Wnt-  -catenin pathway –Frizzled family of receptors –Activation of pathway allows  - catenin to enter nucleus JAK-STAT pathway –Peptide hormone or cytokine receptor coupled to a Jak cytoplasmic tyrosine kinase –Jaks activate STAT transcription factors Hedgehog Pathway –Patched and smoothened co- receptors –Activation of pathway converts Ci txn’l repressor to activator Steroids/Retinoids –Nuclear/DNA binding receptors –Hormone permits entry into nucleus, alters DNA binding conformation, or allows interaction with co-txn factors

Cell Associated Signaling Molecules ECM (ligand) –Fibronectin –Laminin –Type IV collagen Integrins (receptor) CAMs (receptor) Notch Family (receptor) Delta Family (ligand) Eph Family (receptor) Ephrin Family (ligand)

Generalized Signal Transduction

RTK- Ras Pathway GAP Grb2,Shc GEF like Sos GEF

Evolutionary Conservation of Ras Pathway

Examples of RTK Signaling: Photoreceptor Differentiation

sev = sevenless boss = bride of sevenless ro = rough

Examples of RTK Signaling: Vulval Differentiation in C. elegans

Critical Mutations In RTK Pathways Constitutively active receptors Dominant negative receptors Constitutively active Ras Faulty GEFs or GAPs

Smad Pathway

Mesoderm specification –TGF  - activin, Vg1, nodal Ectoderm specification –BMP4, 7 Dorsal specification (Drosophila) –Dpp

Smad Pathway Inhibitors Inhibitory Smads –Bind to smads 1, 5 or 2, 3 in the hypophosphorylated state & prevent interaction with smad4 –Phosphorylation of smads 1,5, 2 & 3 disrupt inhibitory smad interaction and allow smad 4 binding Noggin Chordin –Bind to BMPs and prevent their interaction with receptors

Smad Pathway A More Detailed Look

Wnt -  -catenin Pathway A more detailed look at Wnt signaling

Wnt = Drosophila wingless (wg) + mammalian int-1  -catenin = armadillo Dorsal specification in Xenopus Segment polarity in Drosophila Wnt -  -catenin Pathway

Inhibitors of wnt signaling –Frisbee –Dickkopf –Cerberus Look like extracellular portion of frizzled Bind to wnts and prevent their interaction with frizzled Wnt -  -catenin Pathway Inhibitors

RTK-JAK-Stat pathway

JAK-Stat Pathway Cytokine receptors –Interleukin, Interferon receptors –Blood cell differentiation Chondrocyte differentiation Mammary epithelium

Juxtacrine Signaling: Notch Pathway

Lateral Inhibition Specification of neural precursor cells in Drosophila neurectoderm Blue cell becomes neural precursor – GMC; white ones remain epidermis.

Focal Adhesion Complex

Signaling Through FAs

Signaling Through Cadherin- Associated RTKs

Eph RTK/Cell Adhesion Interactions & Signaling Eph receptor

Apoptotic Pathways