Minor Splicing Factors Zrsr1 and Zrsr2 Essential for Gametogenesis, Early Embryo Development and Conversion of Stem Cells into 2C-Like

Zrsr2 has been attributed a role in splice site recognition of U12 and U2 introns. To better understand the part played by minor splicing during oogenesis and early embryo development, we produced Zrsr2 mutant mice (Zrsr2mu). In Zrsr2mu female oogenesis was blocked at the secondary follicle stage, in a similar way as Zrsr1mu affects spermatogenesis. Zrsr2mu follicles showed altered expression of genes related to gonad development, DNA replication and cell cycle regulation, and altered splicing events involving enrichment of U12-type intron retention (IR). Embryo development was impaired during zygotic gene activation (ZGA) at the 2-cell stage when female Zrsr2mu were crossed with male Zrsr1mu. These embryos showed increased IR in U12-containing genes related to the cell cycle and mitotic nuclear division. Remarkably, both mouse Zrsr1 and Zrsr2 were required for conversion of mouse induced pluripotent stem cells (iPSC) into 2C-like cells. According to our results, Zrsr1 and Zrsr2 are essential during overall chromatin reorganization in the meiotic prophase of meiosis, ZGA and conversion of pluripotent into 2C-like cells.