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. Notably, individual deletion of either or results in variable holoprosencephaly phenotypes in mice, even on a congenic background. In contrast, we find that deletion results in facial widening that correlates with increased HH target gene expression. In addition, deletion in a null background partially ameliorates the craniofacial defects observed in single mutants; a phenotype that persists over developmental time, resulting in significant improvements to a subset of craniofacial structures. This contrasts with HH-dependent phenotypes in other tissues that significantly worsen following combined deletion of and 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.