Zrsr2, zinc finger CCCH-type, RNA binding motif and serine/arginine rich 2, is an essential splicing factor. As a component of both the major and minor spliceosomes, it is involved in 3' splice-site recognition, mediating the splicing of U2-type (major) and U12-type (minor) introns. It plays a significant role in multiple biological processes, and genetic models such as gene-knockout mouse models are valuable for studying its functions [2].

In mouse models, Zrsr2 mutant lines showed blood cell anomalies, and in some lines, oogenesis was blocked at the secondary follicle stage. RNA-seq of Zrsr2 mutant secondary follicles indicated aberrant gene expression and altered alternative splicing events, with enrichment of U12-type intron retention. These events were related to centriole replication, protein phosphorylation, and DNA damage checkpoint, and AS events of 50 meiotic genes were also affected, suggesting Zrsr2 mutations can impede oogenesis and female fertility [1].

In zebrafish, zrsr2-knockout embryos displayed multiple developmental defects starting at 4 days post-fertilization and died after 8 dpf, and the loss of Zrsr2 led to down-regulation of essential metabolic pathways and aberrant retention of minor introns in about one-third of all minor intron-containing genes [2].

In mice with concurrent Zrsr2 mutation and Tet2 loss, it promoted myelodysplastic neoplasm (MDS), presenting peripheral blood cytopenia, splenomegaly, extramedullary hematopoiesis, and multi-lineage dysplasia. Whole-transcriptome analysis in HSPC revealed key alterations in ribosome, inflammation, and migration/motility processes, and the MAPK pathway was the most affected target by mRNA aberrant splicing [3].

In conclusion, Zrsr2 is crucial for the splicing of U12-type introns and is essential for various biological processes such as embryonic development, follicular development, and hematopoiesis. The use of gene-knockout mouse models and other genetic models has significantly contributed to understanding its role in diseases like MDS and its impact on female fertility and embryonic development.