The Role of CDO in Myogenic Differentiation

描述（由申请人提供）：骨骼肌前体的规范和分化受MyoD转录因子家族控制，该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肉形成，但启动这些通路的细胞表面蛋白尚不清楚。CDO是一种在肌肉前体上表达的孤细胞表面受体。缺乏CDO的小鼠骨骼肌发育延迟，而CDO促进体外成肌分化。CDO的功能是在细胞-细胞接触部位发现的复合物的组成部分，该复合物含有几种早生肌蛋白，包括密切相关的受体BOC；细胞粘附分子N-和m -钙粘蛋白；netrin受体，neogenin。CDO通过增强异源二聚化信号激活MyoD，可能是通过诱导其E蛋白伴侣的过度磷酸化，而cadherins和netrin/ neogenin则通过信号激活其他途径。这个复杂的组成部分在它们的一些活动中显示出相互依赖性（即，CDO需要钙粘蛋白，而BOC和neogenin需要CDO）。据推测，细胞-细胞接触部位的多蛋白复合物允许在分化过程中协调调节形态和转录反应的多种信号事件。提出了一种多学科的方法，其总体目标是获得含有cdo的复合物如何调节骨骼肌发育的机械观点。具体目标是：1)确定CDO结合伙伴BOC和neogenin在体内肌肉形成中的作用；2)分析含cdo细胞表面复合物的生化和信号特性；3)分析cdo介导的E蛋白过度磷酸化。这项研究应该阐明骨骼肌发展的基本过程，从而推进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.