Boc modifies the holoprosencephaly spectrum of Cdo mutant mice.
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It is reported here that whereas mice lacking the Cdo paralog Boc do not have HPE, Cdo;Boc double mutants on a largely Cdo-resistant genetic background have lobar HPE with strong craniofacial anomalies and defects in Shh target gene expression in the developing forebrain, therefore Boc is therefore a silent HPE modifier gene in mice.Abstract:
Holoprosencephaly (HPE) is caused by a failure to form the midline of the forebrain and/or midface. It is one of the most common human birth defects, but clinical expression is extremely variable. HPE is associated with mutations in the sonic hedgehog (SHH) pathway. Mice lacking the Shh pathway regulator Cdo (also called Cdon) display HPE with strain-dependent penetrance and expressivity, implicating silent modifier genes as one cause of the variability. However, the identities of potential HPE modifiers of this type are unknown. We report here that whereas mice lacking the Cdo paralog Boc do not have HPE, Cdo;Boc double mutants on a largely Cdo-resistant genetic background have lobar HPE with strong craniofacial anomalies and defects in Shh target gene expression in the developing forebrain. Boc is therefore a silent HPE modifier gene in mice. Furthermore, Cdo and Boc have specific, selective roles in Shh signaling in mammals, because Cdo;Boc double-mutant mice do not display the most severe HPE phenotype seen in Shh-null mice, nor do they have major defects in digit patterning or development of vertebrae, which are also Shh-dependent processes. This is in contrast to reported observations in Drosophila, where genetic removal of the Cdo and Boc orthologs Ihog and Boi results in a complete loss of response to the hedgehog ligand. Therefore, there is evolutionary divergence between mammals and insects in the requirement of the hedgehog pathway for Cdo/Ihog family members, with mammalian development involving additional factors and/or distinct mechanisms at this level of pathway regulation.read more
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Overlapping Roles and Collective Requirement for the Coreceptors GAS1, CDO, and BOC in SHH Pathway Function
Benjamin L. Allen,Benjamin L. Allen,Jane Y. Song,Luisa Izzi,Luisa Izzi,Irene W. Althaus,Jong-Sun Kang,Frédéric Charron,Frédéric Charron,Robert S. Krauss,Andrew P. McMahon +10 more
TL;DR: Evidence is provided that GAS1, CDO, and BOC play overlapping and essential roles during HH-mediated ventral neural patterning of the mammalian neural tube and an early role in cell fate specification of multiple neural progenitors and a later role in motor neuron progenitor maintenance.
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Boc and Gas1 each form distinct Shh receptor complexes with Ptch1 and are required for Shh-mediated cell proliferation
Luisa Izzi,Martin Lévesque,Steves Morin,Dominique Laniel,Brian C. Wilkes,Frédéric Mille,Robert S. Krauss,Andrew P. McMahon,Benjamin L. Allen,Frédéric Charron +9 more
TL;DR: It is shown that, unexpectedly, cerebellar granule neuron progenitors lacking Boc and Cdon, the vertebrate orthologs of Ihog and Boi, still proliferate in response to Hh, and a distinct requirement for ligand-binding components that distinguishes the vertebrates and invertebrate Hh receptor systems is revealed.
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