Notch signaling deficiency underlies age-dependent depletion of satellite cells in muscular dystrophy.
Notch signaling deficiency underlies age-dependent depletion of satellite cells in muscular dystrophy.
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DOI：
10.1242/dmm.015917
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发表时间：
2014-08
影响因子：
4.3
通讯作者：
Kuang S
中科院分区：
文献类型：
--
作者：
Jiang C;Wen Y;Kuroda K;Hannon K;Rudnicki MA;Kuang S
Duchenne肌营养不良症(DMD)是一种毁灭性的疾病，其特征是肌肉萎缩、行动不便和在成年早期死亡。卫星细胞是肌肉干细胞，负责修复和再生受损的肌肉。DMD的一个病理特征是卫星细胞进行性耗竭，导致肌肉修复失败。在这里，我们试图探索Dstrophin突变MDX小鼠卫星细胞消融的分子机制，这是一个公认的DMD模型。最初的肌肉退化激活了卫星细胞，导致MDX幼鼠的卫星细胞数量增加。随之而来的是随着年龄的增长，由于MDX卫星细胞自我更新能力降低，卫星细胞迅速丧失。此外，即使在年轻的mdx小鼠中，卫星细胞的组成也发生了变化，非定向型(Pax7+和Myf5−)卫星细胞的丰度显著减少。利用Notch-Report小鼠，我们发现MDX卫星细胞减少了Notch信号的激活，这被证明是维持卫星细胞静止和自我更新所必需的。同时，MDX原代成肌细胞中Notch1、Notch3、Jag1、Hey1和Heyl的表达减少。最后，我们建立了一个小鼠模型来结构性地激活卫星细胞中的Notch信号，并表明Notch的激活足以挽救MDX卫星细胞的自我更新缺陷。这些结果表明，Notch信号对维持卫星细胞库是必不可少的，而Notch信号的缺失会导致DMD卫星细胞的枯竭。
Duchenne muscular dystrophy (DMD) is a devastating disease characterized by muscle wasting, loss of mobility and death in early adulthood. Satellite cells are muscle-resident stem cells responsible for the repair and regeneration of damaged muscles. One pathological feature of DMD is the progressive depletion of satellite cells, leading to the failure of muscle repair. Here, we attempted to explore the molecular mechanisms underlying satellite cell ablation in the dystrophin mutant mdx mouse, a well-established model for DMD. Initial muscle degeneration activates satellite cells, resulting in increased satellite cell number in young mdx mice. This is followed by rapid loss of satellite cells with age due to the reduced self-renewal ability of mdx satellite cells. In addition, satellite cell composition is altered even in young mdx mice, with significant reductions in the abundance of non-committed (Pax7+ and Myf5−) satellite cells. Using a Notch-reporter mouse, we found that the mdx satellite cells have reduced activation of Notch signaling, which has been shown to be necessary to maintain satellite cell quiescence and self-renewal. Concomitantly, the expression of Notch1, Notch3, Jag1, Hey1 and HeyL are reduced in the mdx primary myoblast. Finally, we established a mouse model to constitutively activate Notch signaling in satellite cells, and show that Notch activation is sufficient to rescue the self-renewal deficiencies of mdx satellite cells. These results demonstrate that Notch signaling is essential for maintaining the satellite cell pool and that its deficiency leads to depletion of satellite cells in DMD.
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影响因子：
4.6
作者：
Lepper, Christoph;Partridge, Terence A.;Fan, Chen-Ming
通讯作者：
Fan, Chen-Ming
DOI：
10.1007/bf01188043
发表时间：
1990-10-01
期刊：
JOURNAL OF NEUROCYTOLOGY
影响因子：
--
作者：
LAMPERTH, L;MANUELIDIS, L;WEBSTER, HD
通讯作者：
WEBSTER, HD
影响因子：
11.8
作者：
Conboy, IM;Rando, TA
通讯作者：
Rando, TA
DOI：
10.1038/nrm3591
发表时间：
2013-06
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
5.2
作者：
Buono, Roberta;Vantaggiato, Chiara;Pisa, Viviana;Azzoni, Emanuele;Bassi, Maria Teresa;Brunelli, Silvia;Sciorati, Clara;Clementi, Emilio
通讯作者：
Clementi, Emilio