Determination and differentiation of the skeletal muscle lineage is controlled by the MyoD family of myogenic transcription factors. These factors, along with another transcription factor, MEF2, autoactivate and crossactivate the expression of each other, resulting in an autoregulatory, positive feedback network that maintains the myogenic phenotype. Determination and differentiation of cells in this lineage also requires specific cellcell interactions between muscle precursors. However, the role of cell surface proteins in myogenesis is poorly understood, and the mechanisms by which events at the cell surface are sensed by the regulatory network of myogenic transcription factors are unknown. CDO is a recently identified cel1 surface glycoprotein that contains five immunoglobulin like repeats followed by three fibronectin type III like repeats in its extracellular region (ECR) and a long intracellular region (ICR) that does not resemble other known proteins. Several lines of evidence, including overexpression studies and the use of dominant negative mutants, strongly indicate that CDO plays an important role in myogenic differentiation and may mediate, at least in part, the cell cell interactions between muscle precursors that are required for myogenesis. Published and preliminary data suggest the following hypothesis: CDO exerts its effects by binding in heterophilic fashion to an unidentified partner protein expressed on the surface of neighboring cells; this interaction results in the generation of intracellular signals that positively regulate the activity of myogenic transcription factors. Whether CDO serves as a ligand, receptor or both is not yet clear, but the CDO ICR is required for its myogenic effects.
The Specific Aims are: 1) to identify proteins that bind to the ECR of CDO and function as CDO ligands and/or receptors; 2) to determine CDO domains that are necessary for its myogenic effects; 3) to identify proteins that interact with the unique ICR of CDO and participate in its ability to mediate myogenesis; and 4) to define mechanisms by which CDO influences the activities of transcription factors of the myogenic regulatory network. The long term goal is to illuminate the molecular basis of CDO function, with particular reference to its role in regulation of differentiation of specific cell lineages during embryogenesis. The proposed work will provide information critical to a molecular understanding of CDO's role in myogenesis and should therefore shed light on fundamental processes by which skeletal muscles develop.
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