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 Δi4/Δi4 larvae showed normal numbers of HSPCs, a recovery mediated by Notch signalling driving gata2b and runx1 expression in HE. However, gata2a Δi4/Δi4 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.
Haematopoietic stem and progenitor cells (HSPCs) maintain the vertebrate blood system throughout life and their emergence from haemogenic endothelium (HE) is tightly regulated by transcription factors such as Gata2. Zebrafish have two orthologues of Gata2, gata2a and gata2b, the latter required for HSPC emergence. Here we deleted a conserved enhancer driving gata2a expression in endothelium (i4 enhancer) and showed that Gata2a is required for HE programming by regulating expression of gata2b and runx1. By 5 days, homozygous gata2a Δi4/Δi4 larvae showed normal numbers of HSPCs, a recovery mediated by Notch signalling driving gata2b expression in HE. However, gata2a Δi4/Δi4 adults showed lymphoedema, susceptibility to infections and marrow hypocellularity, consistent with bone marrow failure of MonoMAC syndrome patients. Thus, Gata2a is required for HE programming and haematopoiesis in the adult. Like MonoMAC syndrome patients, gata2a Δi4/Δi4 mutants developed acute myeloid leukemia. These mutants will be invaluable to explore the pathophysiology of MonoMAC syndrome in vivo.
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