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，其通常是静止的并且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的具体信息很少。我们最近已经确定了两个卫星细胞表面受体，syndecan-3和syndecan-4，这是两个相关的4硫酸乙酰肝素蛋白聚糖家族的成员，是卫星细胞功能的关键调节剂。这些蛋白质由核心I型整合膜蛋白组成，其细胞外结构域用硫酸乙酰肝素糖胺聚糖（GAG）链修饰。多配体蛋白聚糖-3和多配体蛋白聚糖-4两者对于卫星细胞都是功能关键的，如从多配体蛋白聚糖-3-/-和多配体蛋白聚糖-4-/-小鼠的表型中显而易见的。来自多配体蛋白聚糖-4缺失的卫星细胞似乎通常不能活化和增殖。它们不能表达MyoD、肌细胞生成素和肌球蛋白重链（MyHC），但这些小鼠在出生时通常表现正常。与卫星细胞缺陷一致，这些小鼠的肌肉再生严重受损。多配体蛋白聚糖-3-/-小鼠显示出显著不同的表型，具有大量过量的肌核和卫星细胞。肌肉切片显示脂肪和结缔组织浸润以及含有位于中央的细胞核的新生肌纤维。值得注意的是，这两个相关的和共表达的HSPG的无效等位基因表现出明显不同的表型，并似乎调节卫星细胞生理学的不同方面。我们建议：（i）鉴定多配体蛋白聚糖-3-/-和多配体蛋白聚糖-4-/-小鼠中骨骼肌表型的开始;（ii）功能性地表征多配体蛋白聚糖-3和多配体蛋白聚糖-4在骨骼肌再生中的作用;和（iii）鉴定促成观察到的表型的wt、多配体蛋白聚糖-3-/-和多配体蛋白聚糖-4-/-卫星细胞之间的分子差异。这些研究将提供新的见解，并增加了重要的知识，我们的理解调控肌肉再生的卫星细胞细胞外基质和细胞内信号转导通路之间的相互作用。

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.