期刊
DEVELOPMENT
卷 149, 期 17, 页码 -出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.200450
关键词
Splicing factor; dhx38; Erythro-myeloid progenitors; Hematopoietic stem and progenitor cells; Cell cycle; DNA damage
资金
- Ministry of Science and Technology of the People?s Republic of China
- National Natural Science Foundation of China
- [2018YFA0801000]
- [82071010]
- [81670099]
- [81800870]
- [31801041]
- [81870691]
Mutations in Dhx38 lead to defects in chromosome alignment and apoptosis in EMPs and HSPCs, highlighting the importance of alternative splicing in hematopoiesis.
Mutations that occur in RNA-splicing machinery may contribute to hematopoiesis-related diseases. How splicing factor mutations perturb hematopoiesis, especially in the differentiation of erythro-myeloid progenitors (EMPs), remains elusive. Dhx38 is a pre-mRNA splicing-related DEAH box RNA helicase, for which the physiological functions and splicing mechanisms during hematopoiesis currently remain unclear. Here, we report 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 were found to be arrested in mitotic prometaphase, accompanied by a 'grape' karyotype, owing to the defects in chromosome alignment. Abnormal alternatively spliced genes related to chromosome segregation, the microtubule cytoskeleton, cell cycle kinases and DNA damage were present in the dhx38 mutants. Subsequently, EMPs and HSPCs in dhx38 mutants underwent P53-dependent apoptosis. This study provides novel insights into alternative splicing regulated by Dhx38, a process that plays a crucial role in the proliferation and differentiation of fetal EMPs and HSPCs.
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