title: Essential role for ligand-dependent feedback antagonism of vertebrate hedgehog signaling by PTCH1, PTCH2 and HHIP1 during neural patterning.
abstract: Hedgehog (HH) signaling is essential for vertebrate and invertebrate embryogenesis. In Drosophila, feedback upregulation of the HH receptor Patched (PTC; PTCH in vertebrates), is required to restrict HH signaling during development. By contrast, PTCH1 upregulation is dispensable for early HH-dependent patterning in mice. Unique to vertebrates are two additional HH-binding antagonists that are induced by HH signaling, HHIP1 and the PTCH1 homologue PTCH2. Although HHIP1 functions semi-redundantly with PTCH1 to restrict HH signaling in the developing nervous system, a role for PTCH2 remains unresolved. Data presented here define a novel role for PTCH2 as a ciliary localized HH pathway antagonist. While PTCH2 is dispensable for normal ventral neural patterning, combined removal of PTCH2- and PTCH1-feedback antagonism produces a significant expansion of HH-dependent ventral neural progenitors. Strikingly, complete loss of PTCH2-, HHIP1- and PTCH1-feedback inhibition results in ectopic specification of ventral cell fates throughout the neural tube, reflecting constitutive HH pathway activation. Overall, these data reveal an essential role for ligand-dependent feedback inhibition of vertebrate HH signaling governed collectively by PTCH1, PTCH2 and HHIP1.
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Holtz
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Peterson
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Nishi
authors.forename: Steves
authors.initials: S
authors.lastname: Morin
authors.forename: Jane Y
authors.initials: JY
authors.lastname: Song
authors.forename: Frédéric
authors.initials: F
authors.lastname: Charron
authors.forename: Andrew P
authors.initials: AP
authors.lastname: McMahon
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Allen
mesh_terms: D016475:3T3 Cells; D000818:Animals; D019521:Body Patterning; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002642:Chick Embryo; D004622:Embryo, Mammalian / Q000378:metabolism; D025461:Feedback, Physiological; D005260:Female; D018507:Gene Expression Regulation, Developmental; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054259:Neural Tube / Q000378:metabolism*; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D000072082:Patched-2 Receptor; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D002352:Carrier Proteins; C498447:Hhip protein, mouse; D008024:Ligands; D008562:Membrane Glycoproteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D000072082:Patched-2 Receptor; C000606240:Ptch1 protein, mouse; C000606241:Ptch2 protein, mouse; D011956:Receptors, Cell Surface
keywords: Hedgehog; Negative feedback; Neural tube
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