SRSF10 is essential for progenitor spermatogonia expansion by regulating alternative splicing

• Published in: eLife Vol. 11
• Main Authors: Liu, Wenbo, Lu, Xukun, Zhao, Zheng-Hui, Su, Ruibao, Li, Qian-Nan Li, Xue, Yue, Gao, Zheng, Sun, Si-Min Sun, Lei, Wen-Long, Li, Lei, An, Geng, Liu, Hanyan, Han, Zhiming, Ouyang, Ying-Chun, Hou, Yi, Wang, Zhen-Bo, Sun, Qing-Yuan, Liu, Jianqiao
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 10-11-2022; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Alternative Splicing; Analysis; Animals; Cell cycle; Cell Cycle Proteins - metabolism; Cell differentiation; Cell Differentiation - genetics; Chromosomes; Developmental Biology; DNA binding proteins; Fertility; Gene expression; Humans; Male; Meiosis; Mice; Mice, Knockout; Progenitor cells; progenitor spermatogonia; Promyeloid leukemia; Proteins; Proteomes; Repressor Proteins - metabolism; RNA; Scientific equipment and supplies industry; Serine-Arginine Splicing Factors - genetics; Serine-Arginine Splicing Factors - metabolism; Spermatogenesis; Spermatogenesis - genetics; Spermatogonia; Splicing factors; SRSF10; Stem cell transplantation; Stem cells; Stem Cells and Regenerative Medicine; Testes; Transcriptomes; Zinc finger proteins; United States; mouse; stem cells; alternative splicing; developmental biology; regenerative medicine; spermatogenesis; SRSF10; progenitor spermatogonia
• ISSN: 2050-084X; 2050-084X
• 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.