SRSF2扮演着双重角色,作为转录调节因子和可变剪接的关键角色。MyoD+祖细胞中Srsf2的缺失导致小鼠围产期死亡,伴有严重的骨骼肌缺陷。SRSF2缺乏破坏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测序分析揭示了Srsf2缺陷型成肌细胞的显著改变,包括细胞外基质成分的减少,与阿米波样细胞迁移和细胞骨架组织有关的基因表达减少,有丝分裂不规则,过早的分化。值得注意的是,由Srsf2调节的靶标之一是丝氨酸/苏氨酸激酶Aurka。敲除Aurka导致细胞增殖减少,细胞骨架破坏,分化受损,反映了用Srsf2击倒看到的效果。至关重要的是,在Srsf2敲低细胞中引入外源Aurka可显着减轻由Srsf2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的基因中的选择性剪接中的作用,如BIN1、DMPK、FHL1和LDB3。具体来说,包含Bin1外显子17的变体的精确敲除,在Srsf2耗尽后排除,严重破坏C2C12细胞分化。总之,我们的研究为SRSF2在将MyoD祖细胞调控到特定肌肉区域的作用提供了有价值的见解,从而通过调节骨骼肌发育过程中的靶基因和可变剪接来控制它们的分化。
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 Aurka led to reduced cell proliferation, disrupted cytoskeleton, and impaired differentiation, reflecting the effects seen with Srsf2 knockdown. Crucially, the introduction of exogenous Aurka in Srsf2-knockdown cells markedly alleviated the differentiation defects caused by Srsf2 knockdown. Furthermore, our research unveiled the role of Srsf2 in controlling alternative splicing within genes associated with human skeletal muscle diseases, such as BIN1, DMPK, FHL1, and LDB3. Specifically, the precise knockdown of the Bin1 exon17-containing variant, which is excluded following Srsf2 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.