Srsf2-flox Mouse

Srsf2, also known as SC35, is a serine/arginine-rich splicing factor widely expressed in mammalian cells. It plays vital roles in pre-mRNA processing and gene transcription, participating in numerous biological processes such as spermatogenesis, cell-cycle regulation, and DNA damage response [3,4]. It has also been implicated in disease-related pathways, especially in myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) [1,2]. Genetic models, like KO/CKO mouse models, are valuable for studying its functions.

In male germ cell-specific Srsf2 knockout (Srsf2-deleted by Stra8-Cre), mice showed complete infertility and defective spermatogenesis. Srsf2 regulatory networks were found crucial for reproductive development, spermatogenesis, and related events. Srsf2 directly affected the expression and alternative splicing of genes encoding critical spermatogenesis factors [3].

In Srsf2P95H mutant knock-in mice co-expressed with Jak2V617F, reduced red blood cell, neutrophil, and platelet counts were observed, along with attenuated splenomegaly, without bone marrow fibrosis induction. Srsf2P95H also diminished the competitiveness of Jak2V617F mutant hematopoietic stem/progenitor cells [5].

Srsf2P95H in another set of knock-in mice delayed myelofibrosis induced by Jak2V617F, decreased TGFβ1 serum level, and reduced the competitiveness of transplanted Jak2V617F hematopoietic stem cells while preventing their exhaustion. RNA sequencing of megakaryocytes showed an increased number of splicing events when the two mutations were combined, with Srsf2P95H promoting Jak2 exon 14 skipping, generating an inactive JAK2 protein [6].

In conclusion, Srsf2 is essential for mRNA splicing during spermatogenesis and has a significant impact on hematopoietic functions as revealed through mouse model-based research. In disease areas, especially MDS and MPN, Srsf2 mutations play important roles, and studies using KO/CKO mouse models have provided insights into the molecular mechanisms underlying these diseases, which may help develop new therapeutic strategies.