S108: Spatial and Temporal Signaling!Main Ideas - Induction to specify cell fate and pattern!- Cell induction requires an inducer and responder that must be competent !- Sequential induction is key in embryonic development, ex. eye development!- Most embryonic inductions are mediated by secreted signaling molecules (TGFB, hedgehog, FGF, Wnt)!- These paracrine factors can form a gradient, differentially affecting populations of cells!- The final result of these signaling pathways is txn regulation to induce change/cell fate specification and patterning!!- How to instruct a population of cells!- Induction: a process by which one pop'n of cells (inducer) affects the development of another (responder) through signaling!- Ability to respond to the inducing signal= competence!- Two types of inductions!1) Paracrine: involves diffusible molecules!2) Juxtacrine: involves cell contact, membrane associated, = contant-dependent induction!- Eye development!- Optic vesicle= inducer - Head ectoderm is competent to receive the signal and trunk is NOT competent to receive the signal!- Formation of lens dependent on optic vesicle, and w/o it you don't get an eye, but if you move it somewhere else you won't form a lens either.!- Testing whether its para- or juxtacrine!- Put a filter between cells (to prevent contact) --> head ectoderm developed into lens so it's paracrine signaling!- Most embryonic inductions mediated by secreted signaling factors!- Secreted signaling factors can:!- act on remote cells in paracrine fashion!- form gradient, affecting cells differently based on [ ] of signaling factors!- activate intracellular pathways!- 4 Major Signaling Pathways in Embryonic Development 1) Fibroblast growth factor (FGF) 2) Hedgehog (Hh) - NO Hh signaling --> Gli3 is cleaved to produce a txn repressor of Hh target gene!- Activation of pathway: Shh binds to receptor Patched --> alleviates inhibition by Patched on tm protein Smoothened --> unprocess Gli3 protein accumulates in nucleus as a txn activator!- Hh signaling converts Gli from a txn repressor to a txn activator 3) Wnt!- No Wnt signaling --> Bcat sequestered and targeted --> ubiquinated and degraded inproteosome!- Presence of Wnt --> LRP sequesters Dishevelled --> Bcat is free --> acts as a txn regulator 4) TGFB - TGBF fam ligand --> binds R II --> p's R I --> p's to activate Smad --> dimerize (w/universal smad) --> go to nucleus --> txn or repression!!!!!!- Families of ligands that activate TGFB pathway:!- BMP, TGFB, Activin!!!!!!!!!- Paracrine factors for eye induction and molecules to make competent!- Fgf8= signaling factor that can induce the lens!- Pax-6 is req. for head ectoderm to become competent for lens induction!- Optic vesicle grows toward the surface ectoderm --> induce local ectoderm to form lens!- Ov= inducer, inducing molecule= Fgf8!- Only head ectoderm is competent to respond to Fgf9 due in part to Pax6 expression in head (and not trunk) ectoderm!- Sequentional Induction!- signaling back= sequential induction: process by which subsets of cells acquire distinct phenotypes to produce specific factors that act on and change the fate of neighboring cells --> which then affect their neighbors!- key mech for pattern formation!- development= series of inductions!- seq. induction interactions lead to pattern formation!- specification of embryonic axis: A/P, D/V, L/R, specification of axes and elements in an organ!- eye development, neural tube patterning!- Induction on optic vesicle by eye lens to form optic cup - Once lens forms --> signals back and induces optic vesicle for form optic cup !- Lens capsule signals and induces overlying ectoderm to become cornea!!!!!- Neural tube dorsal/ventral patterning!- Spinal cord can be divided into regions that contain specific cell types!- Inductive interactions est. D/V axis!- Inductive factors incl. Shh and BMP4,7 on opp. sides of D/V axis!- Dorsal levels of neural tube exposed to lowest levels of Hh and highest BMPs (activated TGFB signaling) from ectoderm --> neural tube on top will express BMPs too!- Diff [ ]s of these 2 factors determines neurons that will be made!- Shh-expressing notochord induces ventral neural tube!- Notochord induces floor plate (w/o notochord floor plate doesn't form)!- If 2nd notochord put ectopically --> a 2nd ectopic floor plate induced (due to diffusible morphogen= sonic hedgehog)!- Gradients of paracrine factors induce synthesis of different txn factors along the D/V axis of neural tube!- Dep. on [ ] of Hh and BMPs --> diff cells will express diff. types of txn factors --> diff. types of neurons!- Dorsal-ventral patterning of neural tube SUMMARY - Ventral patterning of neural tube induced by Shh secreted by notochord (Hedgehog signaling pathway)!- Dorsal patterning of neural tube induced by BMP4 and 7 secreted by epidermic and roof plate (TGFB signaling pathway)!- Gradients of the 2 paracrine factors on opp. ends of D/V axis result in production of diff. txn factors, which specify diff. neuronal cell fates!- TGFB signaling and disease!- Many diseases that affect skeleton w/TGFB signaling!- Brachydactyly --> too little TGFB signaling or impaired signaling (not enough GDF5)--> improper joint formation!- Too much signaling (ex. you lose Nog= an inhibitor) --> oversignaling of pathway --> Sym1 (digits fuse)!- Hedgehog Signaling and Disease!- Pallister-Hall syndrome: truncated Gli3 repressor!- have Gli only as a repressor!- Findings: polydactyly (no fusion), often more than 6 digits!- Greig cephalopolysyndactyly: haplo-insufficiency of Gli3!- No Gli3 being made --> not repressing or activating!- Findings: megalocephaly, broad thumb, additional digit, fusion of digits 2-5, duplicated big toe!- Gorlin's syndrome/basal cell nervous syndrome!- Haploinsufficiency of Patched, overactions of Hh signaling!- Mut in patch so you can't inhibit Smoothened so Smoothened can activate signaling even if hedgehog isn't present!- Findings: tumors, cysts because overaction of Hh signaling --> cell prolif/overgrowth!- Holoprosencephaly cyclopia!- Mutations in hedgehog!- Structures of body get closer to midline, affects facial features and brain formation, often not viable!- Ch modification allows better signal diffusion!- Hedgehog has to modified by Ch --> allows it to diffuse better --> if you don't have this proper modifcation --> Hh can't diffuse cell --> not all cells get the signal!- Ex. cyclopic lamb exposed in utero to jervine alkaloid (inhibits Ch syn. in
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