Role of Syndecans in Satellite Cell Function

描述(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，位于肌肉纤维的基底膜和肌膜之间。由于这些细胞只占肌肉细胞核总数的1-6%，关于卫星细胞功能调节机制的具体信息知之甚少。我们最近发现了两个卫星细胞表面受体，Syndecan-3和Syndecan-4，这是4个硫酸乙酰肝素蛋白多糖家族中的两个相关成员，它们是卫星细胞功能的关键调节因子。这些蛋白由一个核心型I型完整膜蛋白组成，其胞外结构域由硫酸乙酰肝素糖胺聚糖(GAG)链修饰。从Syndecan-3-/-和Syndecan-4-/-小鼠的表型可以看出，Syndecan-3和Syndecan-4对卫星细胞的功能至关重要。Syndecan-4缺失的卫星细胞似乎一般不能激活和增殖。它们不表达MyoD、肌肉生成素和肌球蛋白重链(MyHC)，但这些小鼠在出生时通常看起来正常。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，有大量的肌核和卫星细胞。肌肉切片显示脂肪和结缔组织渗入，以及含有中央定位核的新生肌纤维。值得注意的是，这两个相关的和共同表达的HSPG的零等位基因表现出显著不同的表型，似乎调节卫星细胞生理学的不同方面。我们建议：(I)确定syndecan-3-/-和syndecan-4-/-小鼠骨骼肌表型的起始；(Ii)从功能上表征syndecan-3和syndecan-4在骨骼肌再生中所起的作用；以及(Iii)识别wt、syndecan-3-/-和syndecan-4-/-卫星细胞之间的分子差异。这些研究将为我们理解卫星细胞外基质和细胞内信号转导通路之间的相互作用调节肌肉再生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.