Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Key Laboratory for Reproductive Medicine of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Elife. 2022 Nov 10;11:e78211. doi: 10.7554/eLife.78211.
Alternative splicing expands the transcriptome and proteome complexity and plays essential roles in tissue development and human diseases. However, how alternative splicing regulates spermatogenesis remains largely unknown. Here, using a germ cell-specific knockout mouse model, we demonstrated that the splicing factor is essential for spermatogenesis and male fertility. In the absence of SRSF10, spermatogonial stem cells can be formed, but the expansion of Promyelocytic Leukemia Zinc Finger (PLZF)-positive undifferentiated progenitors was impaired, followed by the failure of spermatogonia differentiation (marked by KIT expression) and meiosis initiation. This was further evidenced by the decreased expression of progenitor cell markers in bulk RNA-seq, and much less progenitor and differentiating spermatogonia in single-cell RNA-seq data. Notably, SRSF10 directly binds thousands of genes in isolated THY spermatogonia, and depletion disturbed the alternative splicing of genes that are preferentially associated with germ cell development, cell cycle, and chromosome segregation, including , , , , , and . These data suggest that SRSF10 is critical for the expansion of undifferentiated progenitors by regulating alternative splicing, expanding our understanding of the mechanism underlying spermatogenesis.
可变剪接扩大了转录组和蛋白质组的复杂性，并在组织发育和人类疾病中发挥着重要作用。然而，可变剪接如何调节精子发生在很大程度上仍是未知的。在这里，我们使用了一种生殖细胞特异性敲除小鼠模型，证明了剪接因子 SRSF10 对于精子发生和雄性生育力是必不可少的。在缺乏 SRSF10 的情况下，精原干细胞可以形成，但是多能性髓系白血病锌指蛋白 (PLZF)阳性未分化祖细胞的扩增受到了损害，随后精原细胞分化（由 KIT 表达标记）和减数分裂起始失败。这进一步通过 bulk RNA-seq 中祖细胞标志物的表达减少，以及单细胞 RNA-seq 数据中祖细胞和分化精原细胞明显减少得到证实。值得注意的是，SRSF10 可以直接结合分离的 THY 精原细胞中的数千个基因，并且 SRSF10 的缺失会干扰与生殖细胞发育、细胞周期和染色体分离优先相关的基因的可变剪接，包括 、 、 、 、 、 和 。这些数据表明，SRSF10 通过调节可变剪接对于未分化祖细胞的扩增至关重要，扩展了我们对精子发生机制的理解。
