Mutations that occur in RNA splicing machinery may contribute to hematopoietic-related diseases. How splicing factor mutants perturb hematopoiesis, especially in the erythro-myeloid progenitors (EMP) process, remains elusive. Dhx38, a pre-mRNA splicing-related DEAH box RNA helicase, whose physiological function and splicing mechanisms during hematopoiesis currently remain unclear. Here we present that Dhx38 exerts a broad effect on definitive EMPs as well as the differentiation and maintenance of hematopoietic stem and progenitor cells (HSPCs). In dhx38 knockout zebrafish, EMPs and HSPCs are found arrested in mitotic prometaphase, accompanied by a ‘grape’ karyotype, due to the defects in chromosome alignment. Abnormal alternative spliced genes related to chromosome segregation, microtubule cytoskeleton, cell cycle kinase, and DNA damage are present in the dhx38 mutants. Subsequently, their EMPs and HSPCs undergo p53-dependent apoptosis. This study provides novel insights into alternative splicing regulated by Dhx38, a process that plays a critical role in proliferation and differentiation of fetal EMPs and HSPCs.
Dhx38 regulates the maintenance and differentiation of erythro-myeloid progenitors and hematopoietic stem cells by alternative splicing
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