Molecular Dissection of Myoblast Fusion In Muscle Development and Regeneration

 描述（由申请方提供）：胚胎发育期间和成年肌肉损伤后骨骼肌的形成需要成肌细胞融合形成多核肌纤维。最近，我们发现了一种新的肌肉特异性膜蛋白，命名为Myomaker，它控制脊椎动物成肌细胞在胚胎发育和成年期的融合。Myomaker在融合过程中表达于胚胎成肌细胞的细胞表面，此后下调。类似地，Myomaker在肌肉卫星细胞中响应于损伤而上调，伴随着它们在肌肉再生期间的融合。成肌细胞中Myomaker的过表达显著增强融合，成纤维细胞中的强制表达促进与成肌细胞的融合。相反，小鼠中Myomaker的遗传破坏由于缺乏多核肌纤维而导致围产期死亡，并且成体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进展，并将使这一过程的机制基础的详细分子解剖成为可能。Myomaker属于在其他细胞类型中表达的相关膜蛋白的小家族，这表明细胞-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发挥其促融合活性的过程中的其他成分。从这些研究中收集的见解不仅将揭示细胞间融合的基本机制，而且还将对理解肌肉疾病和恢复患病肌肉功能的新治疗策略的潜在发展具有重要意义。

 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.