Merosin and laminin in myogenesis; Specific requirement for merosin in myotube stability and survival
Merosin and laminin in myogenesis; Specific requirement for merosin in myotube stability and survival
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DOI：
10.1083/jcb.134.6.1483
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发表时间：
1996-09-01
影响因子：
7.8
通讯作者：
Engvall, E
中科院分区：
文献类型：
--
作者：
Vachon, PH;Loechel, F;Engvall, E
层粘连蛋白(层粘连蛋白-L；α1-β1-γ1)是已知的促进成肌细胞增殖的蛋白。融合和肌管形成。Merosin(层粘连蛋白-2和-4；α2-β1/β2-Gamma 1)是骨骼肌基底膜中主要的层粘连蛋白变体：影响其结构或表达的遗传缺陷是某些类型的先天性肌营养不良的原因。然而，Merosin在肌肉中作用的确切性质仍不清楚。我们建立了一个体外系统，利用人RD和小鼠C2C12成肌细胞系及其克隆变体来研究Merosin和Laminin在肌肉发生中的作用。在与多核肌管有效融合的亲本细胞中，Merosin的表达作为分化的函数上调，而层粘连蛋白的表达下调。来自融合缺陷克隆的细胞不表达这两种蛋白质，但添加到培养基中的层粘连蛋白或Merosin诱导了它们的融合。融合但形成不稳定肌管的克隆变异体表达层粘连蛋白，但不表达硫蛋白。外源Merosin将这些肌管转化为稳定的表型，而层粘连蛋白则没有作用。最有效地纠正肌管不稳定性的方法是将Merosinα2链基因导入Merosin缺陷细胞。最后，Merosin似乎通过防止细胞凋亡来促进肌管的稳定性。因此，这些研究确定了Merosin在成肌细胞融合和肌肉细胞存活中的新的生物学功能；此外，这些研究解释了Merosin缺乏引起的先天性肌营养不良症的一些致病事件，并为进一步研究这种疾病的分子机制提供了体外模型。
Laminin (laminin-l; alpha 1-beta 1-gamma 1) is known to promote myoblast proliferation. fusion, and myotube formation. Merosin (laminin-2 and -4; alpha 2-beta 1/beta 2-gamma 1) is the predominant laminin variant in skeletal muscle basement membranes: genetic defects affecting its structure or expression are the causes of some types of congenital muscular dystrophy. However, the precise nature of the functions of merosin in muscle remain unknown. We have developed an in vitro system that exploits human RD and mouse C2C12 myoblastic cell lines and their clonal variants to study the roles of merosin and laminin in myogenesis. In the parental cells, which fuse efficiently to multinucleated myotubes, merosin expression is upregulated as a function of differentiation while laminin expression is downregulated. Cells from fusion-deficient clones do not express either protein, but laminin or merosin added to the culture medium induced their fusion. Clonal variants which fuse, but form unstable myotubes, express laminin but not merosin. Exogenous merosin converted these myotubes to a stable phenotype, while laminin had no effect. Myotube instability was corrected most efficiently by transfection of the merosin-deficient cells with the merosin alpha 2 chain cDNA. Finally, merosin appears to promote myotube stability by preventing apoptosis. Hence, these studies identify novel biological functions for merosin in myoblast fusion and muscle cell survival; furthermore, these explain some of the pathogenic events observed in congenital muscular dystrophy caused by merosin deficiency and provide in vitro models to further investigate the molecular mechanisms of this disease.