WTAP Function in Sertoli Cells Is Essential for Sustaining the Spermatogonial Stem Cell Niche

Abstract

Summary Sertoli cells are the major component of the spermatogonial stem cell (SSC) niche; however, regulatory mechanisms in Sertoli cells that dictate SSC fate decisions remain largely unknown. Here we revealed features of the N 6 -methyladenosine (m 6 A) mRNA modification in Sertoli cells and demonstrated the functions of WTAP, the key subunit of the m 6 A methyltransferase complex in spermatogenesis. m 6 A-sequencing analysis identified 21,909 m 6 A sites from 15,365 putative m 6 A-enriched transcripts within 6,122 genes, including many Sertoli cell-specific genes. Conditional deletion of Wtap in Sertoli cells resulted in sterility and the progressive loss of the SSC population. RNA sequencing and ribosome nascent-chain complex-bound mRNA sequencing analyses suggested that alternative splicing events of transcripts encoding SSC niche factors were sharply altered and translation of these transcripts were severely dysregulated by Wtap deletion. Collectively, this study uncovers a novel regulatory mechanism of the SSC niche and provide insights into molecular interactions between stem cells and their cognate niches in mammals.

The Latest Research Progress of m6A Modification and Its Writers, Erasers, Readers in Infertility: A Review

“…Moreover, by making WTAP ineffective, expression levels of GDNF, which is essential for maintaining the SCC pool, were also found to be down-regulated, therefore, sertoli cells cannot maintain the SSC pool, leading to SSC depletion. In addition, transcripts associated with SCC maintenance and spermatogonia differentiation in sertoli cells are severely affected by gene transcription and translation changes (Jia et al, 2020). Knockout of WTAP was found to alter splicing events in sertoli cells, with a large number of abnormal splicing events occurring in m 6 A-rich genes.…”

“…During spermatogenesis, its gene was found to be significantly expressed in mouse Sertoli cells. In Sertoli cells, WTAP was found to significantly affect SSC proliferation and self-renewal (Jia et al, 2020). By conditionally eliminating WTAP in supporting cells, it was found that SSC was progressively lost and eventually led to infertility (Jia et al, 2020).…”

“…In Sertoli cells, WTAP was found to significantly affect SSC proliferation and self-renewal (Jia et al, 2020). By conditionally eliminating WTAP in supporting cells, it was found that SSC was progressively lost and eventually led to infertility (Jia et al, 2020). WTAP knockout was also found to lead to progressive loss of SSC and depletion of germ cells, which reduced sperm concentrations in mice, thereby contributing to the sterile phenotype of mice.…”

“…If the WTAP function is lost, splicing events in genes that regulate spermatogenesis are altered, which eventually affects spermatogenesis. The WTAP-mediated m 6 A regulates mRNA transcription and translation, thereby coordinating the expression of essential genes, so that SSC maintenance of sertoli cells and differentiation of spermatogonia occur normally (Jia et al, 2020).…”

The Roles of RNA N6-Methyladenosine in Regulating Stem Cell Fate

“…METTL3 deletion in germ cells prevented spermatogonial differentiation and meiosis (Xu et al, 2017). WTAP-mediated m 6 A modification sustained the SSC niche and governed normal spermatogenesis (Jia et al, 2020).…”