The spliceosome factor sart3 regulates hematopoietic stem/progenitor cell development in zebrafish through the p53 pathway
- Zhao, Y., Wu, M., Li, J., Meng, P., Chen, J., Huang, Z., Xu, J., Wen, Z., Zhang, W., Zhang, Y.
- Cell Death & Disease 12: 906 (Journal)
- Registered Authors
- Meng, Ping, Wen, Zilong, Wu, Mei, Zhang, Wenqing, Zhang, Yiyue
- MeSH Terms
- Alternative Splicing/genetics
- Base Sequence
- Cell Proliferation
- DEAD-box RNA Helicases/genetics
- DEAD-box RNA Helicases/metabolism*
- Hematopoietic Stem Cells/cytology*
- Hematopoietic Stem Cells/metabolism*
- Models, Biological
- RNA Splicing Factors/genetics
- RNA Splicing Factors/metabolism*
- Signal Transduction*
- Tumor Suppressor Protein p53/metabolism*
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- 34611130 Full text @ Cell Death Dis.
Zhao, Y., Wu, M., Li, J., Meng, P., Chen, J., Huang, Z., Xu, J., Wen, Z., Zhang, W., Zhang, Y. (2021) The spliceosome factor sart3 regulates hematopoietic stem/progenitor cell development in zebrafish through the p53 pathway. Cell Death & Disease. 12:906.
Hematopoietic stem cells (HSCs) possess the potential for self-renew and the capacity, throughout life, to differentiate into all blood cell lineages. Yet, the mechanistic basis for HSC development remains largely unknown. In this study, we characterized a zebrafish smu471 mutant with hematopoietic stem/progenitor cell (HSPC) defects and found that sart3 was the causative gene. RNA expression profiling of the sart3smu471 mutant revealed spliceosome and p53 signaling pathway to be the most significantly enriched pathways in the sart3smu471 mutant. Knock down of p53 rescued HSPC development in the sart3smu471 mutant. Interestingly, the p53 inhibitor, mdm4, had undergone an alternative splicing event in the mutant. Restoration of mdm4 partially rescued HSPC deficiency. Thus, our data suggest that HSPC proliferation and maintenance require sart3 to ensure the correct splicing and expression of mdm4, so that the p53 pathway is properly inhibited to prevent definitive hematopoiesis failure. This study expands our knowledge of the regulatory mechanisms that impact HSPC development and sheds light on the mechanistic basis and potential therapeutic use of sart3 in spliceosome-mdm4-p53 related disorders.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes