hnRNPM cooperates with BCAS2 to modulate alternative splicing during oocyte development.

Abstract

Growing oocytes accumulate maternal mRNA to support subsequent meiotic maturation and maternal-to-zygotic transition. However, the regulatory mechanisms governing the fate of these maternal mRNAs remain largely unknown. Here, we identified heterogeneous nuclear ribonucleoprotein M (hnRNPM) as a critical regulator of pre-mRNA alternative splicing during mouse oocyte development. Genetic ablation of hnRNPM leads to severe cytoplasmic defects, meiotic arrest, and complete female infertility. Using SCAN-seq, we uncovered novel transcript isoforms and systematically characterized hnRNPM-regulated alternative splicing events. Furthermore, LACE-seq revealed hnRNPM-binding sites at single-nucleotide resolution in oocytes, linking its RNA-binding activity to splicing fidelity. Additionally, hnRNPM interacts with BCAS2, a known splicing factor critical for oocyte development, and modulates its binding to pre-mRNA loci to precisely control the alternative splicing. Overall, our study not only uncover an essential role of hnRNPM in mammalian oocyte development and female fertility but also unveils a critical regulatory network governing alternative splicing during oocyte development.