hnRNPC Functions with HuR to Regulate Alternative Splicing in an m6A-Dependent Manner and is Essential for Meiosis

Abstract

N6-methyladenosine (m6A) and its reader proteins are involved in pre-mRNA processing and play a variety of roles in numerous biological processes. However, much remains to be understood about the regulation of m6A and the function of its specific readers during meiotic processes. Here, this study shows that the potential m6A reader protein hnRNPC is essential for both male and female meiosis in mice. Germ cell-specific knockout of Hnrnpc causes meiotic arrest at pachynema in male mice. Specifically, hnRNPC-deficient males show abnormal meiosis initiation and defective meiotic progression, ultimately leading to meiotic arrest at the pachytene stage. Interestingly, hnRNPC-null females show similar meiotic defects to males. Mechanistically, this study discovers that in male germ cells, hnRNPC works with HuR to directly bind and modulate alternative splicing of meiotic-related genes (e.g., Sycp1, Brca1, and Smc5) in an m6A-dependent manner during spermatogenesis. Collectively, these findings reveal hnRNPC as a critical factor for meiosis and contribute to a mechanistic understanding of the hnRNPC-HuR interaction in alternative splicing of mRNAs during germ cell development.