期刊
COMMUNICATIONS BIOLOGY
卷 3, 期 1, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s42003-020-0798-3
关键词
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资金
- MRC MHU [MC_UU_12009, MC_UU_12009/8]
- NIHR Oxford BRC
- John Fell Fund [131/030, 101/517]
- EPA fund [CF182, CF170]
- Wolfson Foundation [18272]
- MRC/BBSRC/EPSRC grant [MR/K015777X/1]
- WIMM Strategic Alliance [G0902418, MC_UU_12025]
- British Heart Foundation (BHF Oxford CoRE)
- British Heart Foundation (BHF IBSR Fellowship) [FS/13/50/30436]
- Wellcome Trust [WT102345/Z/13/Z]
- MRC HIU
- MRC [MC_UU_12009/8] Funding Source: UKRI
Gata2 is a key transcription factor required to generate Haematopoietic Stem and Progenitor Cells (HSPCs) from haemogenic endothelium (HE); misexpression of Gata2 leads to haematopoietic disorders. Here we deleted a conserved enhancer (i4 enhancer) driving pan-endothelial expression of the zebrafish gata2a and showed that Gata2a is required for HE programming by regulating expression of runx1 and of the second Gata2 orthologue, gata2b. By 5 days, homozygous gata2a(Delta i4/Delta i4) larvae showed normal numbers of HSPCs, a recovery mediated by Notch signalling driving gata2b and runx1 expression in HE. However, gata2a(Delta i4/Delta i4) adults showed oedema, susceptibility to infections and marrow hypo-cellularity, consistent with bone marrow failure found in GATA2 deficiency syndromes. Thus, gata2a expression driven by the i4 enhancer is required for correct HE programming in embryos and maintenance of steady-state haematopoietic stem cell output in the adult. These enhancer mutants will be useful in exploring further the pathophysiology of GATA2-related deficiencies in vivo. Dobrzycki et al delete a conserved enhancer that drives endothelial expression of the transcription factor Gata2a in Zebrafish and find that it is required for programming of haemogenic endothelium and for maintenance of haematopoietic stem cells in the adult. These data may help understanding Gata2 deficiency syndromes in humans.
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