title: Boc and Gas1 each form distinct Shh receptor complexes with Ptch1 and are required for Shh-mediated cell proliferation.
abstract: Hedgehog (Hh) proteins regulate important developmental processes, including cell proliferation and differentiation. Although Patched acts as the main Hh receptor in Drosophila, Hh signaling absolutely requires the additional Hh-binding proteins Ihog and Boi. Here we show that, unexpectedly, cerebellar granule neuron progenitors (CGNPs) lacking Boc and Cdon, the vertebrate orthologs of Ihog and Boi, still proliferate in response to Hh. This is because in their absence, Gas1, an Hh-binding protein not present in Drosophila, mediates Hh signaling. Consistently, only CGNPs lacking all three molecules-Boc, Cdon, and Gas1-have a complete loss of Hh-dependent proliferation. In a complementary manner, we find that a mutated Hh ligand that binds Patched1 but not Boc, Cdon, or Gas1 cannot activate Hh signaling. Together, this demonstrates an absolute requirement for Boc, Cdon, and Gas1 in Hh signaling and reveals a distinct requirement for ligand-binding components that distinguishes the vertebrate and invertebrate Hh receptor systems.
authors.affiliation: Molecular Biology of Neural Development, Institut de Recherches Cliniques de Montréal, Canada.
authors.forename: Luisa
authors.initials: L
authors.lastname: Izzi
authors.forename: Martin
authors.initials: M
authors.lastname: Lévesque
authors.forename: Steves
authors.initials: S
authors.lastname: Morin
authors.forename: Dominique
authors.initials: D
authors.lastname: Laniel
authors.forename: Brian C
authors.initials: BC
authors.lastname: Wilkes
authors.forename: Frédéric
authors.initials: F
authors.lastname: Mille
authors.forename: Robert S
authors.initials: RS
authors.lastname: Krauss
authors.forename: Andrew P
authors.initials: AP
authors.lastname: McMahon
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Allen
authors.forename: Frédéric
authors.initials: F
authors.lastname: Charron
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000502:physiology; D018797:Cell Cycle Proteins / Q000502:physiology*; D049109:Cell Proliferation; D002531:Cerebellum / Q000166:cytology / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D058851:GPI-Linked Proteins / Q000502:physiology; D053823:Hedgehog Proteins / Q000502:physiology*; D007124:Immunoenzyme Techniques; D007074:Immunoglobulin G / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000502:physiology*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*
chemical_list: C510745:Boc protein, mouse; C510744:Cdon protein, mouse; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D058851:GPI-Linked Proteins; C501180:Gas1 protein, mouse; D053823:Hedgehog Proteins; D007074:Immunoglobulin G; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; C465570:Shh protein, mouse