ROLE OF ZRSR PROTEINS IN HEMATOPOIETIC DEVELOPMENT AND RNA SPLICING

Abstract

Inactivating alterations of splicing factor gene, ZRSR2, are observed in ~10% of patients with myelodysplastic syndromes. ZRSR2 plays a significant role in splicing of U12-type introns. To further uncover its precise function in pre-mRNA splicing and hematopoietic development, we generated constitutional Zrsr2 knockout mice. We demonstrated that ablation of Zrsr2 in murine myeloid precursors led to abnormal retention of U12-type introns. However, Zrsr2 KO mice displayed normal hematopoiesis. To understand this unexpected observation, we explored the role of Zrsr1, a close-homolog of Zrsr2, and found it cooperates with Zrsr2 in regulating splicing of U12-type introns. We also demonstrated that mis-splicing of U12-type introns of MAPK9 and MAPK14 genes in human and murine cells lacking ZRSR proteins impacted their protein expression. Overall, we highlight the functional role of murine ZRSR1 in hematopoietic cells and underline the importance of taking ZRSR1 into account when replicating loss of human ZRSR2 activity in murine model.