Role of Syndecans in Satellite Cell Function

描述（由申请人提供）：骨骼肌是终末分化的，因此不能再生。负责肌肉再生的细胞被称为卫星细胞，它们通常是静止的，位于肌纤维的基底膜和肌膜之间。由于这些细胞仅占肌核总数的1-6%，因此关于调节卫星细胞功能的机制知之甚少。我们最近发现了两个卫星细胞表面受体，syndecan-3和syndecan-4，它们是4个硫酸肝素蛋白聚糖家族的两个相关成员，是卫星细胞功能的关键调节剂。这些蛋白由核心I型整体膜蛋白组成，其胞外结构域被硫酸肝素糖胺聚糖（GAG）链修饰。从syndecan-3-/-和syndecan-4-/-小鼠的表型可以明显看出，syndecan-3和syndecan-4对卫星细胞的功能至关重要。从syndecan-4空细胞中提取的卫星细胞一般不能活化和增殖。它们不能表达MyoD、myoggenin和myosin重链（MyHC），但这些小鼠在出生时表现一般正常。与卫星细胞缺陷一致，这些小鼠的肌肉再生严重受损。Syndecan-3-/-小鼠表现出明显不同的表型，具有大量过量的核和卫星细胞。肌肉切片显示脂肪和结缔组织浸润，新生肌纤维包含位于中央的细胞核。值得注意的是，这两种相关和共表达的HSPGs的零等位基因表现出显著不同的表型，并似乎调节卫星细胞生理的不同方面。我们建议：(i)确定syndecan-3-/-和syndecan-4-/-小鼠骨骼肌表型的发病；（ii）功能表征syndecan-3和syndecan-4在骨骼肌再生中的作用；（iii）确定wt、syndecan-3-/-和syndecan-4-/-卫星细胞之间的分子差异，这些差异有助于观察到的表型。这些研究将为我们理解卫星细胞胞外基质和细胞内信号转导途径之间的相互作用对肌肉再生的调节提供新的见解和重要的知识。

DESCRIPTION (provided by applicant): Skeletal muscle is terminally differentiated and as such, cannot regenerate. The cells responsible for muscle regeneration are known as satellite cells, which are normally quiescent and reside between the basement membrane and the sarcolemma of the muscle fiber. Because these cells comprise only 1-6% of the total number of muscle nuclei, little specific information is known regarding the mechanisms that regulate satellite cell function. We have recently identified two satellite cell surface receptors, syndecan-3 and syndecan-4, which are two related members of a family of 4 heparan sulfate proteoglycans that are critical regulators of satellite cell function. These proteins are comprised of a core type I integral membrane protein whose extracellular domain is decorated with heparan sulfate glycosaminoglycan (GAG) chains. Both syndecan-3 and syndecan-4 are functionally critical for satellite cells as is evident from the phenotypes of syndecan-3-/- and syndecan-4-/- mice. Satellite cells from syndecan-4 nulls appear to be generally incapable of activation and proliferation. They fail to express MyoD, myogenin and myosin heavy chain (MyHC), yet these mice appear generally normal at birth. Consistent with a satellite cell defect, muscle regeneration in these mice is severely impaired. Syndecan-3-/- mice display a strikingly different phenotype, having a large excess of myonuclei and satellite cells. Muscle sections reveal fatty and connective tissue infiltrates as well as nascent myofibers containing centrally located nuclei. It is noteworthy that null alleles for these two related and co-expressed HSPGs exhibit remarkably distinct phenotypes and appear to regulate distinct aspects of satellite cell physiology. We propose to: (i) identify the onset of the skeletal muscle phenotypes in syndecan-3-/- and syndecan-4-/- mice; (ii) functionally characterize the roles syndecan-3 and syndecan-4 play in skeletal muscle regeneration; and, (iii) identify molecular differences between wt, syndecan-3-/- and syndecan-4-/- satellite cells contributing to the observed phenotypes. These studies will provide new insights and add significant knowledge to our understanding of the regulation of muscle regeneration regulated by interactions between the satellite cell extracellular matrix and intracellular signal transduction pathways.