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Hedgehog signaling pathway Indian hedgehog: expressed in gut and chondrocytes Desert hedgehog: expressed in sertoli cells of the testes Sonic hedgehog: Involved in many developmental processes. Best characterized
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Gilbert, Figure 6.24
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Shh and Cholesterol Amino-terminal portion is secreted and functional (also palmitoylated) Cholesterol is required for the cleavage of Shh (N-terminal is active peptide) Patched protein requires cholesterol in order to function (sterol sensing domain) Mutations or chemicals that interfere with cholesterol biosynthesis cause abnormalities akin to SHH knockout animals
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Patched protein (Ptc) Is the Shh “receptor” 12 Transmembrane domains Negative regulator of Shh signaling 2 Vertebrate homologs Ptc-1 and Ptc-2 Ptc-1 is upregulated in response to Shh Ptc has a sterol sensing domain (SSD)
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Smoothened protein (Smo) 7 transmembrane domains (like G-protein coupled receptors) Positive regulator of the Shh pathway Does not bind to Shh but is signaling component of the receptor complex Smo is constitutively active in the absence of Ptc
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Cubitus interruptus (Ci)/Gli transcription factor family Zn++ finger transcription factors Recognize a 9bp consensus sequence in the promoters of several Hh target genes In the absense of Hh the full length protein (Ci-155) is in the cytoplasm and gets processed into a 75 kD N-terminal repressor form (Ci-75)
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Modificaiton of Ci in Drosophila From Munroe, et. al. (1999) Exp. Cell Res. 253:25-33
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Ci-75 repressor generation is: Triggered in part by protein kinase A (Pka) phosphorylation of the C-terminus Possible participation of Slimb, a ubiquitin targeting protein and the proteosome Cleavage of Ci-155 is blocked by the presence of Hedgehog (Smo signaling)
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Hedgehog activation of “positively regulating” Ci-155 Facilitated by a serine/threonine kinase called fused Antagonized by “Supressor of fused” Su(fu) Mutant embryos for Fu or Ci have defects resembling Hh deficiency Pka or Ptc mutants display ectopic expression of Hh target genes CBP/p300 is a co-activator for Ci-155
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Role of microtuble association Cos-2 tethers Ci and Fu to the microtubles Cos-2 is a negative regulator of the pathway Hh signaling leads to Cos-2 dissociation and phosphorylation of both Fu and Cos-2 Unanswered questions: –How does Smo signal to the microtuble associated complex? –What exactly is in the complex?
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Hedgehog signaling pathway From Munroe, et. al. (1999) Exp. Cell Res. 253:25-33
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Vertebrate versions of Ci (the Gli proteins) Behave differently in this pathway than Ci does in Drosophila Gli-1, Gli-2 and Gli-3 appear to be transcriptionally regulated in response to Shh See Munroe et. al. (1999) for several assorted speculations
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Evidence for Sonic Hedgehog involvement in development Mouse knockout results in abnormal limb development and cyclopia Gli-3/Ci mutations lead to Grieg's cephalopolysyndactyly and other inherited diseases Activating mutations can cause cancers (basal cell carcinomas-epidermal)
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Wnt/wingless pathway Ligands, Wnt-secreted glycoproteins –At least 16 members of the Wnt ligand family Receptors are relatives of Frizzled (Frz) –11 Frizzled homologs in vertebrates Soluble Frz related proteins (Frps) exist –Antagonists of wnt signaling –Proposed to play a role in neural development
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Wnt signal transduction Fig 6.23 of Gilbert
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Negative regulators of wnt signals Glycogen synthase kinase (GSK)-3 –Binds and phosphorylates several proteins in the wnt pathway to downregulate -catenin Adenomatous polyposis coli (APC) –Tumor suppressor in which mutations eliminate binding sites for Axin and -catenin Axin: Binds APC, -catenin, GSK-3 and dishevelled (Dvl) –Facilitates phosphorylation of APC and -catenin by GSK-3
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A closer look at -catenin regulation From Polakis (2000) Genes Dev. 14:1837-1851
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-catenin mutations in tumors Table 1 From Polakis (2000) Genes Dev. 14:1837-1851
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Clustered mutations in wnt signaling components affect negative interactions -catenin mutations in the N-terminal region affect amino acids necessary for its phosphorylation dependent interaction with protein degradation machinery APC mutations affect axin and -catenin binding Axin mutations truncate the protein thus eliminating -catenin binding sites
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The wnt pathway is loaded with proto- oncogenes and tumor suppressors Figure 1 From Polakis (2000) Genes Dev. 14:1837-1851
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Fibroblast Growth Factors (FGF) 19-22 FGF family members (FGF-1 called acidic FGF, FGF-2 called basic FGF) Some lack signal sequences for secretion Contain heparin/heparan sulfate binding domains (critical for the function of some FGFs) Four FGF receptors. Several FGFs bind to more than one FGF receptor with high affinity FGFRs are transmembrane tyrosine kinases
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Evidence for FGF involvement in development: KO mice FGF2: defects in vascular systems FGF3: inner ear and tail development FGF4: early post-implantation lethality FGF5 and FGF7: Abnormal hair phenotype FGF8: Early embryonic lethality. Conditional KO showed effect on brain development FGF10: lung and limb development
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FGF Receptor KO phenotypes FGFR-1: Postimplantation embryonic lethal with vertebral malformations FGFR-2: Postimplantation embryonic lethal with abnormal limb development FGFR-3: Defective chondrocyte generation FGFR-4: Perfectly normal Websites 6.2 and 6.6 deal with FGF & FGFR
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Facts on Retinoic Acid RA is a teratogen, causes birth defects Interfering with RA biosynthesis causes developmental abnormalities linked to Hox gene expression Exerts it effect through the retinoic acid receptors (RAR) which dimerizes with other steroid receptors to activate transcription Important in development of limbs, neural tube and in anterior-posterior patterning
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