LSM7 Coordinates scaRNA-Mediated snRNA Modification to Ensure Spliceosome Fidelity and Spermatogonial Stem Cell Differentiation

Spermatogenesis requires precise spatial and temporal regulation of RNA splicing, orchestrated by both the major (U1, U2, and U4/U6/U5) and minor (U11, U12, and U4atac/U6atac/U5) spliceosomal small nuclear ribonucleoproteins (snRNPs), yet their function during germ cell development remain poorly defined. Here, we elucidate the essential function of LSM7, a component of the LSM2-8 complex, in snRNP biogenesis and the process of spermatogenesis. Our results demonstrate that LSM7 governs the stability of U6 small nuclear RNA (snRNA) within Cajal bodies and directly interacts with scaRNA2, scaRNA13, and scaRNA17 to modulate 2′-O-methylation (2′-O-Me) and pseudouridylation (Ψ) modifications of U2 and U12 snRNAs. Loss of LSM7 results in defective nuclear localization and reduced stability of U6, U2, U5, and U12 snRNAs, destabilization of their corresponding snRNP complexes, and aberrant splicing events, notably affecting mutually exclusive exons (MXE) and exon skipping (SE). These splicing defects lead to translational dysregulation, ultimately impairing the differentiation of spermatogonial stem cells (SSCs) into spermatogonia. Our findings identify LSM7 as a pivotal regulator linking scaRNA-guided snRNA modifications, spliceosomal fidelity, and the determination of spermatogonial stem cell fate, offering important mechanistic insights into the post-transcriptional regulation of male germ cell development.