A zebrafish model for MonoMAC syndrome identifies an earlier role for gata2 in haemogenic endothelium programming and generation of haematopoietic stem cells
Research output: Working paper
Colleges, School and Institutes
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 gata2aΔi4/Δi4 larvae showdnormal numbers of HSPCs, a recovery mediated by Notch signalling driving gata2b expression in HE. However, gata2aΔi4/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, gata2aΔi4/Δi4 mutants developed acute myeloid leukemia. These mutants will be invaluable to explore the pathophysiology of MonoMAC syndrome in vivo.
|Number of pages||38|
|Publication status||Published - 9 Jan 2019|
- gata2a, gata2b, haemogenic endothelium, haematopoietic stem cells, haploinsufficiency, bone marrow failure, acute myeloid leukemia