The Role of CDO in Myogenic Differentiation

描述（由申请人提供）：骨骼肌前体的特化和分化由MyoD家族的转录因子控制，MyoD家族与其他转录因子合作协调肌肉特异性基因的表达并融合成多核肌纤维。几种信号通路调节这些因子的活性并促进肌生成，但启动这些通路的细胞表面蛋白尚不清楚。CDO是在肌肉前体上表达的孤儿细胞表面受体。缺乏CDO的小鼠显示骨骼肌发育延迟，并且CDO在体外促进肌源性分化。CDO作为在细胞-细胞接触位点发现的复合物的组分起作用，该复合物含有几种促肌原蛋白，包括密切相关的受体BOC;细胞粘附分子N-和M-钙粘蛋白;以及netrin受体再生蛋白。CDO信号通过增强的异源二聚化激活MyoD，可能是通过诱导其E蛋白伴侣的过度磷酸化，而钙粘蛋白和netrin/再生蛋白信号激活其他途径。这种复合体的组成部分在其某些活动中表现出相互依赖性（即，CDO需要钙粘蛋白，并且BOC和再生蛋白需要CDO）。据推测，多蛋白复合物在网站的细胞-细胞接触允许不同的信号转导事件，调节形态和转录反应，以协调在分化过程中。提出了一种多学科的方法，其总体目标是获得含CDO的复合物如何调节骨骼肌发育的机制观点。具体目标是：1）鉴定CDO结合配偶体BOC和再生蛋白在体内肌生成中的作用; 2）分析含CDO的细胞表面复合物的生物化学和信号传导性质;和3）分析CDO介导的E蛋白的过度磷酸化。这项研究应该阐明骨骼肌发育的基本过程，从而提出改善骨骼肌疾病治疗的潜在策略。

DESCRIPTION (provided by applicant): 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.