Molecular Dissection of Myoblast Fusion In Muscle Development and Regeneration

 描述(申请人提供)：骨骼肌在胚胎发育期间的形成和成年肌肉的损伤需要成肌细胞的融合以形成多核肌纤维。最近，我们发现了一种新的肌肉特异性膜蛋白，称为Myomaker，它控制脊椎动物胚胎发生和成年期间的成肌细胞融合。Myomaker在胚胎成肌细胞融合过程中表达于细胞表面，之后表达下调。同样，在肌肉再生过程中，Myomaker在肌肉卫星细胞中表达上调，伴随着它们的融合。Myomaker在成肌细胞中的过度表达显著促进了融合，而在成纤维细胞中的强制表达则促进了与成肌细胞的融合。相反，小鼠Myomaker基因的破坏会导致围产期死亡，原因是缺乏多核肌肉纤维，成年卫星细胞中的条件性基因缺失完全阻止了肌肉再生。Myomaker的发现为成肌细胞融合提供了新的途径，并将使详细的分子解剖这一过程的机制基础成为可能。Myomaker属于一个相关的膜蛋白小家族，在其他类型的细胞中也有表达，这表明了细胞-细胞融合的一般机制。该项目的目标是确定Myomaker驱动成肌细胞融合的精确分子机制，并确定Myomaker发挥融合活性的过程的其他组件。从这些研究中收集到的见解不仅将阐明细胞间融合的基本机制，而且将对理解肌肉疾病和潜在地开发新的治疗策略以恢复患病肌肉的功能具有重要意义。

 DESCRIPTION (provided by applicant): The formation of skeletal muscle during embryonic development and following injury to adult muscle requires fusion of myoblasts to form multinucleated myofibers. Recently, we discovered a novel muscle-specific membrane protein, named Myomaker, that controls vertebrate myoblast fusion during embryogenesis and adulthood. Myomaker is expressed on the cell surface of embryonic myoblasts during fusion and is down- regulated thereafter. Similarly, Myomaker is up-regulated in muscle satellite cells in response to injury, concomitant with their fusion during muscle regeneration. Over-expression of Myomaker in myoblasts dramatically enhances fusion and forced expression in fibroblasts promotes fusion with myoblasts. Conversely, genetic disruption of Myomaker in mice causes perinatal death due to an absence of multi- nucleated muscle fibers and conditional gene deletion in adult satellite cells completely prevents muscle regeneration. The discovery of Myomaker provides a new inroad into myoblast fusion and will enable the detailed molecular dissection of the mechanistic basis of this process. Myomaker belongs to a small family of related membrane proteins that are expressed in other cell types, suggesting a general mechanism for cell-cell fusion. The goals of this project are to define the precise molecular mechanism whereby Myomaker drives myoblast fusion and to identify additional components of the process through which Myomaker exerts its fusogenic activity. The insights gleaned from these studies will shed light not only on the fundamental mechanisms of intercellular fusion but will also have important implications for understanding muscle disease and for the potential development of new therapeutic strategies for restoration of function to diseased muscle.