PUBLICATION

The spliceosome factor sart3 regulates hematopoietic stem/progenitor cell development in zebrafish through the p53 pathway

Authors
Zhao, Y., Wu, M., Li, J., Meng, P., Chen, J., Huang, Z., Xu, J., Wen, Z., Zhang, W., Zhang, Y.
ID
ZDB-PUB-211007-2
Date
2021
Source
Cell Death & Disease   12: 906 (Journal)
Registered Authors
Meng, Ping, Wen, Zilong, Wu, Mei, Zhang, Wenqing, Zhang, Yiyue
Keywords
none
Datasets
GEO:GSE182560
MeSH Terms
  • RNA Splicing Factors/genetics
  • RNA Splicing Factors/metabolism*
  • DEAD-box RNA Helicases/genetics
  • DEAD-box RNA Helicases/metabolism*
  • Spliceosomes/metabolism*
  • Apoptosis
  • Animals
  • Mutation/genetics
  • Alternative Splicing/genetics
  • Signal Transduction*
  • Base Sequence
  • Hematopoietic Stem Cells/cytology*
  • Hematopoietic Stem Cells/metabolism*
  • Models, Biological
  • Tumor Suppressor Protein p53/metabolism*
  • Zebrafish/metabolism*
  • Cell Proliferation
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
(all 19)
PubMed
34611130 Full text @ Cell Death Dis.
Abstract
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
Figures
Figure Gallery (6 images)
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
sart3sm471/+; sart3szy4/+standard conditionsDay 4
sart3sm471/+; sart3szy4/+standard conditionsDay 4
sart3sm471/+; sart3szy4/+standard conditionsDay 4
sart3sm471/+; sart3szy4/+standard conditionsDay 4
sart3sm471/sm471standard conditions26+ somites
sart3sm471/sm471standard conditionsLong-pec
sart3sm471/sm471standard conditionsLong-pec
sart3sm471/sm471standard conditionsPec-fin
sart3sm471/sm471standard conditionsPec-fin
sart3sm471/sm471standard conditionsPec-fin
1 - 10 of 69
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
la2TgTransgenic Insertion
    sm471
      		Point Mutation
      szy4
        		Indel
        zdf1
          		Point Mutation
          1 - 4 of 4
          Show
          Human Disease / Model
          No data available
          Sequence Targeting Reagents
          Target Reagent Reagent Type
          sart3CRISPR2-sart3CRISPR
          tp53MO4-tp53MRPHLNO
          1 - 2 of 2
          Show
          Fish
          Fish
          la2Tg
          la2Tg + MO4-tp53
          sart3sm471/sm471
          sart3sm471/sm471; la2Tg
          sart3sm471/sm471; la2Tg + MO4-tp53
          sart3sm471/+; sart3szy4/+
          sart3szy4/szy4
          WT
          1 - 8 of 8
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          Antibodies
          Name Type Antigen Genes Isotypes Host Organism
          Ab4-gapdhmonoclonal
            		IgGRabbit
            Ab8-brdumonoclonal
              		IgG1Mouse
              Ab11-tp53monoclonalIgGMouse
              Ab18-gfppolyclonal
                		IgGGoat
                1 - 4 of 4
                Show
                Orthology
                No data available
                Engineered Foreign Genes
                Marker Marker Type Name
                EGFPEFGEGFP
                1 - 1 of 1
                Show
                Mapping
                No data available
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                Citation
                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.