The Hedgehog Co-Receptor BOC Differentially Regulates SHH Signaling During Craniofacial Development

The Hedgehog (HH) pathway controls multiple aspects of craniofacial development. HH ligands signal through the canonical receptor PTCH1, and three co-receptors– GAS1, CDON and BOC. Together, these co-receptors are required during embryogenesis to mediate proper HH signaling. Here we investigated the individual and combined contributions of GAS1, CDON and BOC to HH-dependent mammalian craniofacial development. Individual deletion of either Gas1 or Cdon results in variable holoprosencephaly phenotypes, characterized by the failure to divide and form the telencephalon and midfacial structures. In contrast, we find that Boc deletion results in facial widening consistent with increased HH pathway activity. Additionally, the deletion of Boc in a Gas1 null background partially rescues the craniofacial defects observed in Gas1 single mutants; a phenotype that persists over developmental time. This contrasts with HH-dependent phenotypes in other tissues that significantly worsen following combined deletion of Gas1 and Boc . Mechanistically, BOC selectively restricts neural crest-derived mesenchymal proliferation. Together, these data indicate that BOC acts as a multi-functional regulator of HH signaling during craniofacial development, alternately promoting or restraining HH pathway activity in a tissue-specific fashion. Summary statement Here we identify dual, tissue-specific roles for the Hedgehog co-receptor BOC in both the promotion and antagonism of Hedgehog signaling during craniofacial development.