CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
Lin He's Academician Workstation of New Medicine and Clinical Translation in Jining Medical University, Jining Medical University, Jining, China.
Elife. 2024 Sep 9;13:RP98175. doi: 10.7554/eLife.98175.
SRSF2 plays a dual role, functioning both as a transcriptional regulator and a key player in alternative splicing. The absence of Srsf2 in MyoD + progenitors resulted in perinatal mortality in mice, accompanied by severe skeletal muscle defects. SRSF2 deficiency disrupts the directional migration of MyoD progenitors, causing them to disperse into both muscle and non-muscle regions. Single-cell RNA-sequencing analysis revealed significant alterations in Srsf2-deficient myoblasts, including a reduction in extracellular matrix components, diminished expression of genes involved in ameboid-type cell migration and cytoskeleton organization, mitosis irregularities, and premature differentiation. Notably, one of the targets regulated by Srsf2 is the serine/threonine kinase Aurka. Knockdown of led to reduced cell proliferation, disrupted cytoskeleton, and impaired differentiation, reflecting the effects seen with knockdown. Crucially, the introduction of exogenous Aurka in -knockdown cells markedly alleviated the differentiation defects caused by knockdown. Furthermore, our research unveiled the role of Srsf2 in controlling alternative splicing within genes associated with human skeletal muscle diseases, such as , , , and . Specifically, the precise knockdown of the exon17-containing variant, which is excluded following depletion, profoundly disrupted C2C12 cell differentiation. In summary, our study offers valuable insights into the role of SRSF2 in governing MyoD progenitors to specific muscle regions, thereby controlling their differentiation through the regulation of targeted genes and alternative splicing during skeletal muscle development.
SRSF2 具有双重功能，既是转录调控因子，也是可变剪接的关键参与者。MyoD + 祖细胞中 Srsf2 的缺失导致小鼠围产期死亡，并伴有严重的骨骼肌缺陷。SRSF2 缺失破坏了 MyoD 祖细胞的定向迁移，导致它们分散到肌肉和非肌肉区域。单细胞 RNA-seq 分析显示 Srsf2 缺陷的成肌细胞发生显著变化，包括细胞外基质成分减少、参与阿米巴样细胞迁移和细胞骨架组织的基因表达减少、有丝分裂异常以及过早分化。值得注意的是，Srsf2 调控的一个靶标是丝氨酸/苏氨酸激酶 Aurka。敲低 导致细胞增殖减少、细胞骨架破坏和分化受损，反映了 敲低的影响。至关重要的是，外源性 Aurka 的引入显著缓解了 敲低引起的分化缺陷。此外，我们的研究揭示了 Srsf2 在控制与人类骨骼肌疾病相关基因的可变剪接中的作用，如 、 、 和 。具体来说，精确敲低 外显子 17 包含的变体，该变体在 耗尽后被排除，严重破坏了 C2C12 细胞分化。总之，我们的研究深入了解了 SRSF2 在控制 MyoD 祖细胞向特定肌肉区域分化中的作用，通过调节靶向基因和骨骼肌发育过程中的可变剪接来控制其分化。
