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Hema Bye-A-Jee, Dhamayanthi Pugazhendhi, Samuel Woodhouse, Patrick Brien, Rachel Watson, Martin Turner, Jennifer Pell
Laboratory of Cell Signalling, The Babraham Institute, Cambridge, UK.
Present address: European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Wellcome Genome Campus, Hinxton, Cambridge, UK.
Skelet Muscle. 2018 Dec 7;8(1):37. doi: 10.1186/s13395-018-0183-9.
Members of the ZFP36 family of RNA-binding proteins regulate gene expression post-transcriptionally by binding to AU-rich elements in the 3'UTR of mRNA and stimulating mRNA degradation. The proteins within this family target different transcripts in different tissues. In particular, ZFP36 targets myogenic transcripts and may have a role in adult muscle stem cell quiescence. Our study examined the requirement of ZFP36L1 and ZFP36L2 in adult muscle cell fate regulation.
We generated single and double conditional knockout mice in which Zfp36l1 and/or Zfp36l2 were deleted in Pax7-expressing cells. Immunostained muscle sections were used to analyse resting skeletal muscle, and a cardiotoxin-induced injury model was used to determine the regenerative capacity of muscle.
We show that ZFP36L1 and ZFP36L2 proteins are expressed in satellite cells. Mice lacking the two proteins in Pax7-expressing cells have reduced body weight and have reduced skeletal muscle mass. Furthermore, the number of satellite cells is reduced in adult skeletal muscle and the capacity of this muscle to regenerate following muscle injury is diminished.
ZFP36L1 and ZFP36L2 act redundantly in myogenesis. These findings add further intricacy to the regulation of the cell fate of Pax7-expressing cells in skeletal muscle by RNA-binding proteins.
ZFP36 家族的 RNA 结合蛋白成员通过结合 mRNA 3'UTR 中的 AU 丰富元件并刺激 mRNA 降解,在后转录水平上调节基因表达。该家族内的蛋白质在不同组织中靶向不同的转录本。特别是,ZFP36 靶向肌源性转录本,可能在成体肌肉干细胞静止中发挥作用。我们的研究检查了 ZFP36L1 和 ZFP36L2 在成体肌肉细胞命运调节中的需求。
我们生成了单和双条件敲除小鼠,其中 Zfp36l1 和/或 Zfp36l2 在 Pax7 表达细胞中被删除。使用免疫染色的肌肉切片分析静止的骨骼肌,并使用心脏毒素诱导的损伤模型来确定肌肉的再生能力。
我们表明 ZFP36L1 和 ZFP36L2 蛋白在卫星细胞中表达。在 Pax7 表达细胞中缺乏这两种蛋白质的小鼠体重减轻,骨骼肌质量减少。此外,成年骨骼肌中的卫星细胞数量减少,并且这种肌肉在肌肉损伤后再生的能力降低。
ZFP36L1 和 ZFP36L2 在成肌作用中具有冗余作用。这些发现为 RNA 结合蛋白对骨骼肌中 Pax7 表达细胞的细胞命运的调节增加了更多的复杂性。