ZFIN ID: ZDB-PUB-110811-32
Dominant-negative C/ebpalpha and polycomb group protein Bmi1 extends short-lived hematopoietic stem/progenitor cells lifespan and induces lethal dyserythropoiesis
Zhou, T., Wang, L., Zhu, K.Y., Dong, M., Xu, P.F., Chen, Y., Chen, S.J., Chen, Z., Deng, M., and Liu, T.X.
Date: 2011
Source: Blood   118(14): 3842-52 (Journal)
Registered Authors: Chen, Yi, Chen, Zhu, Deng, Min, Dong, Mei, Liu, Ting Xi, Xu, Peng-Fei, Zhu, Kang-Yong
Keywords: none
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • CCAAT-Enhancer-Binding Protein-alpha/genetics*
  • CCAAT-Enhancer-Binding Protein-alpha/metabolism
  • Cell Proliferation
  • Cell Survival
  • Cells, Cultured
  • Embryo, Nonmammalian/abnormalities
  • Embryo, Nonmammalian/blood supply
  • Erythropoiesis*
  • Gene Expression Regulation, Developmental*
  • Hematopoietic Stem Cells/cytology*
  • Hematopoietic Stem Cells/metabolism
  • Hematopoietic System/embryology*
  • Hematopoietic System/metabolism
  • Nuclear Proteins/genetics*
  • Nuclear Proteins/metabolism
  • Polycomb Repressive Complex 1
  • Zebrafish/embryology*
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
PubMed: 21828130 Full text @ Blood

The primitive hematopoietic stem/progenitor cells (HSPCs) during embryonic hematopoiesis are thought to be short-lived (SL) with limited self-renewal potential. The fate and consequence of these short-lived HSPCs, once reprogrammed into “long-lived” in a living animal body, remain unknown. Here we show that targeted expression of a dominant-negative C/ebpα (C/ebpαDN) in the primitive SL-HSPCs during zebrafish embryogenesis extends their life span, allowing them to survive to later developmental stage to colonize the definitive hematopoietic sites, where they undergo a proliferative expansion followed by erythropoietic dysplasia and embryonic lethality because of circulation congestion. Mechanistically, C/ebpαDN binds to a conserved C/EBP-binding motif in the promoter region of bmi1 gene, associated with a specific induction of bmi1 transcription in the transgenic embryos expressing C/ebpαDN. Targeted expression of Bmi1 in the SL-HSPCs recapitulates nearly all aberrant phenotypes induced by C/ebpαDN, whereas knockdown of bmi1 largely rescues these abnormalities. The results indicate that Bmi1 acts immediately downstream of C/ebpαDN to regulate the survival and self-renewal of HSPCs and contribute to the erythropoietic dysplasia.