How Do Cells Communicate? • Communication in early development occurs over short distances – Embryos are small • Can influence – cell behavior • shape, migration, division and growth – molecular activity • gene expression • Inducing and responding cells • Only certain cells can respond (competent cells) Are Signals Species Specific? • Spemann and Schotté (1932) • Interspecies induction • Reciprocal transplantation between future oral ectoderm regions of newt and frog gastrulae • Induction by underlying mesenchymal tissue works across species • Specific outcome is determined by the responding tissue What Kinds of Signals Are Sent Between Cells? • Some diffuse over short distances • Not blocked by filters of certain size – No cell contact • Paracrine factors – From cells or ECM What Kinds of Signals Are Sent Between Cells? • Some require cell contact • Blocked by filters which prevent contact • Juxtacrine factors • Contact of cell membrane molecules or ECM Paracrine Signaling Mechanisms • Four major families of signals – FGF (fibroblast growth factors), EGF, PDGF – Hh (hedgehog) – Wnt (wingless) – TGF-b (transforming growth factor beta) and BMPs (bone morphogenetic proteins), activins • Synthesized and secreted by inducing cell • Received by receptor on surface of responding cell • Activate signal transduction pathways – From bound receptor to nucleus General Themes of Signal Transduction • Cascade of protein interaction steps ligand – At each step protein activity is modified • Mechanisms of altering protein activity: – Conformational change – Phosphorylation of an amino acid (or other type of covalent modification) – Proteolytic cleavage receptor – Association with other proteins • These may – Activate enzymatic activity (e.g., phosphorylation) – Change subcellular location – Change stability gene regulation I. FGF/RTK Pathway • Fibroblast growth factor = signal • RTK = receptor – tyrosine kinase • Result of activation – Autophosphorylation – Other phosphorylation I. FGF/RTK Pathway • Then through a GTP switch protein to activated MAP kinase cascade (MEK, ERK) • Activates transcription factors and gene expression I. FGF/RTK Pathway • Example of an RTK pathway – Mammalian c-kit receptor is present on spermatogonia – Sertoli cells promote proliferation of spermatogonia by secreting KL (kit ligand = “stem cell factor”) II. TGF-b/Smad Pathway • TGF -b type molecule is signal • Binding to receptor induces dimerization • Activated receptor I/II phosphorylates Smads II. TGF-b/Smad Pathway • Smads dimerize to form transcription factors • Which Smads depends on which signal III. Wnt/Frz Pathway • Wnt is signal • Frizzled is receptor • Activated Frz activates disheveled III. Wnt/Frz Pathway • Disheveled blocks GSK-3 • Active GSK-3 keeps APC complex together, degrading b-catenin • When blocked, b-catenin escapes to nucleus and forms transcription factor • Also affects cytoskeleton and Ca++ release IV. Hh/Ptc Pathway • Hedgehog = signal • Patched = receptor • Patched is bound to smoothened • Upon Hh binding, smoothened is activated IV. Hh/Ptc Pathway • Smoothened blocks proteins that cut Ci (cubitus interruptus) and releases Ci from MTs • Cut fragment is repressor • Uncut is activator Summary of Pathways FGF etc. .