Hesr1 and Hesr3 are essential to generate undifferentiated quiescent satellite cells and to maintain satellite cell numbers
Hesr1 and Hesr3 are essential to generate undifferentiated quiescent satellite cells and to maintain satellite cell numbers
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DOI：
10.1242/dev.067165
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发表时间：
2011-11-01
期刊：
影响因子：
4.6
通讯作者：
Yamamoto, Hiroshi
中科院分区：
文献类型：
--
作者：
Fukada, So-ichiro;Yamaguchi, Masahiko;Yamamoto, Hiroshi
卫星细胞是骨骼肌干细胞，在出生后发育过程中分裂为生长中的肌纤维提供新的肌核，然后在成年骨骼肌中维持未分化的静止状态。这种状态被认为对于卫星细胞的维持至关重要，但其分子调控尚不清楚。我们发现 Hesr1 (Hey1) 和 Hesr3 (Heyl)（已知的 Notch 靶基因）仅在卫星细胞的骨骼肌中同时表达。在Hesr1和Hesr3单敲除小鼠中，没有观察到卫星细胞或肌肉再生潜力的明显异常。然而，Hesr1/3 双敲除小鼠在出生后发育过程中，未分化静止卫星细胞的生成受到损害。因此，成肌蛋白（MyoD 和肌细胞生成素）和增殖蛋白 (Ki67) 在成体卫星细胞中表达。与体内结果一致，Hesr1/3 缺失的成肌细胞在体外产生很少的 Pax7(+) MyoD 未分化细胞。此外，即使在对照小鼠中卫星细胞数量稳定后，Hesr1/3双敲除小鼠中的卫星细胞数量也逐渐减少，并且观察到年龄依赖性再生缺陷。体内结果表明，Hesr1/3 双敲除小鼠中卫星细胞数量减少的原因是过早分化，而不是细胞死亡。这些结果表明 Hesr1 和 Hesr3 对于成体卫星细胞的生成和骨骼肌稳态的维持至关重要。
Satellite cells, which are skeletal muscle stem cells, divide to provide new myonuclei to growing muscle fibers during postnatal development, and then are maintained in an undifferentiated quiescent state in adult skeletal muscle. This state is considered to be essential for the maintenance of satellite cells, but their molecular regulation is unknown. We show that Hesr1 (Hey1) and Hesr3 (Heyl) (which are known Notch target genes) are expressed simultaneously in skeletal muscle only in satellite cells. In Hesr1 and Hesr3 single-knockout mice, no obvious abnormalities of satellite cells or muscle regenerative potentials are observed. However, the generation of undifferentiated quiescent satellite cells is impaired during postnatal development in Hesr1/3 double-knockout mice. As a result, myogenic (MyoD and myogenin) and proliferative (Ki67) proteins are expressed in adult satellite cells. Consistent with the in vivo results, Hesr1/3-null myoblasts generate very few Pax7(+) MyoD-undifferentiated cells in vitro. Furthermore, the satellite cell number gradually decreases in Hesr1/3 double-knockout mice even after it has stabilized in control mice, and an age-dependent regeneration defect is observed. In vivo results suggest that premature differentiation, but not cell death, is the reason for the reduced number of satellite cells in Hesr1/3 double-knockout mice. These results indicate that Hesr1 and Hesr3 are essential for the generation of adult satellite cells and for the maintenance of skeletal muscle homeostasis.