Effects of <i>Zrsr2</i> Mutations in Mice Oogenesis, Peripheral Blood Cells and Muscle Strength

Abstract

ZRSR2 is a splicing factor essential for 3’ss recognition of U12-type introns and is frequently mutated in myeloid malignancies and in several tumors. To explore the biological role of ZRSR2 we generated three Zrsr2 mutant mice with deletions localized immediately after the AUG initiation and in two splicing sensitive elements present in the two zinc finger domains. The three Zrsr2 mutant mice exhibited muscle weakness, blood cell anomalies, and in the 2 lines with zinc finger mutations, oogenesis was blocked at the secondary follicle stage. RNA-seq of Zrsr2mu follicles showed aberrations in gene expression and biological pathways, and showed altered alternative splicing (AS) events involving enrichment of U2 and U12-type intron retention (IR), suggesting a functional crosstalk between the major and minor spliceosomes. These results suggest that ZRSR2 is essential for efficient U12 intron splicing and reveals that AS regulation of U12 introns constitute a potential underlying mechanism governing oogenesis.