Specification and differentiation of skeletal muscle precursors is controlled by the MyoD family of transcription factors, which cooperate with additional transcription factors to coordinate expression of muscle-specific genes and fusion into multinucleated myofibers. Several signaling pathways regulate the activity of these factors and promote myogenesis, but the cell surface proteins that initiate such pathways are not well understood. CDO is an orphan cell surface receptor expressed on muscle precursors. Mice lacking CDO display delayed skeletal muscle development, and CDO promotes myogenic differentiation in vitro. CDO functions as a component of a complex found at sites of cell-cell contact that contains several promyogenic proteins, including the closely related receptor, BOC; the cell adhesion molecules, N- and M-cadherin; and the netrin receptor, neogenin. CDO signals to activate MyoD via enhanced heterodimerization, likely by inducing hyperphosphorylation of its E protein partners, while cadherins and netrin/ neogenin signal to activate additional pathways. The components of this complex display interdependence in some of their activities (i.e., CDO requires cadherins, and BOC and neogenin require CDO). It is hypothesized that a multiprotein complex at sites of cell-cell contact permits diverse signaling events that regulate both morphological and transcriptional responses to be coordinated during differentiation. A multidisciplin- ary approach is proposed with the overall goal of gaining a mechanistic view of how CDO-containing complexes regulate skeletal muscle development.
The Specific Aims are: 1) to identify the roles of the CDO binding partners, BOC and neogenin, in myogenesis in vivo; 2) to analyze biochemical and signaling properties of CDO-containing cell surface complexes; and 3) to analyze CDO-mediated hyperphosphorylation of E proteins. This research should shed light on fundamental processes by which skeletal muscles develop and therefore advance potential strategies for improved treatment of skeletal muscle diseases.
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