The cell-surface receptor CDO is required for efficient embryonic myogenesis and facial midline development

The MyoD family of basic helix-loop-helix transcription factors must heterodimerize with E-proteins in order to transactivate their target genes. Determination and differentiation of the skeletal muscle lineage is controlled by a positive feedback network, which is comprised of the MyoD family and the MEF-2 proteins. This also requires cell-cell interactions between myogenic precursors; however the identities of the cell-surface proteins that mediate this phenomenon are unknown. CDO, a member of the Ig superfamily, is a component of a cell-surface receptor that forms at points of cell-cell contact to positively regulate differentiation of myoblast cell lines. I report here that mice lacking CDO have delayed myogenesis. In addition, CDO functions to activate the myogenic bHLHs post-translationally by targeting the E-protein binding partner resulting in a shift of its dimerization equilibrium toward active heterodimers. The laboratory has determined that, the Cdo gene is, in turn, a transcriptional target of MyoD. Thus, a positive feedback network loop exists between the CDO receptor complex at the cell surface and myogenic transcription factors in the nucleus. This provides an attractive mechanism to link the requirement for cell-cell interactions between myogenic precursors and the transcription factors that regulate skeletal myogenesis.; Holoprosencephaly (HPE), the most common developmental defect of the forebrain and midface, is caused by a failure to delineate the midline in these structures. Despite the identification of several HPE genes, its genetic basis is largely unknown. Furthermore, the phenotype of affected individuals is highly variable, even within pedigrees. Facial defects in HPE range from cyclopia and proboscis in severe cases to solitary median maxillary central incisor in individuals with microforms of HPE. Cdo is highly expressed in the frontonasal and maxillary processes of the developing mouse embryo, structures that contain signaling centers that pattern the face. Mice homozygous for targeted mutations of Cdo display the hallmark facial defects associated with microforms of HPE. This is the first example of a mouse mutant with this phenotype, implicating a new family of receptors in development of the facial midline and suggesting a potential role for CDO in the pathogenesis and expressivity of HPE in humans.