Stem Cell Institute , University of Minnesota, Minneapolis, MN 55455, USA; Department of Genetics, Cell Biology, and Development , University of Minnesota, Minneapolis, MN 55455, USA.
Stem Cell Institute , University of Minnesota, Minneapolis, MN 55455, USA.
Cell Rep. 2018 Feb 20;22(8):2118-2132. doi: 10.1016/j.celrep.2018.01.077.
Circadian rhythms regulate cell proliferation and differentiation; however, little is known about their roles in myogenic differentiation. Our synchronized differentiation studies demonstrate that myoblast proliferation and subsequent myotube formation by cell fusion occur in circadian manners. We found that one of the core regulators of circadian rhythms, Cry2, but not Cry1, is critical for the circadian patterns of these two critical steps in myogenic differentiation. This is achieved through the specific interaction between Cry2 and Bclaf1, which stabilizes mRNAs encoding cyclin D1, a G1/S phase transition regulator, and Tmem176b, a transmembrane regulator for myogenic cell fusion. Myoblasts lacking Cry2 display premature cell cycle exit and form short myotubes because of inefficient cell fusion. Consistently, muscle regeneration is impaired in Cry2 mice. Bclaf1 knockdown recapitulated the phenotypes of Cry2 knockdown: early cell cycle exit and inefficient cell fusion. This study uncovers a post-transcriptional regulation of myogenic differentiation by circadian rhythms.
昼夜节律调节细胞增殖和分化；然而，它们在肌发生分化中的作用知之甚少。我们的同步分化研究表明，成肌细胞的增殖和随后通过细胞融合形成肌管是按照昼夜节律发生的。我们发现，昼夜节律的核心调节剂之一 Cry2，但不是 Cry1，对于肌发生分化的这两个关键步骤的昼夜节律模式至关重要。这是通过 Cry2 与 Bclaf1 之间的特异性相互作用实现的，该相互作用稳定了编码 cyclin D1（G1/S 期过渡调节剂）和 Tmem176b（肌生成细胞融合的跨膜调节剂）的 mRNA。缺乏 Cry2 的成肌细胞表现出过早的细胞周期退出，并由于融合效率低下而形成短肌管。一致地，Cry2 敲除小鼠的肌肉再生受损。Bclaf1 敲低再现了 Cry2 敲低的表型：细胞周期提前退出和融合效率低下。这项研究揭示了昼夜节律对肌发生分化的转录后调控。
