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Redundant mechanisms driven independently by RUNX1 and GATA2 for hematopoietic development

Authors: 
Bresciani E, Carrington B, Yu K, Kim EM, Zhen T, Guzman VS, Broadbridge E, Bishop K, Kirby M, Harper U, Wincovitch S, Dell'Orso S, Sartorelli V, Sood R, Liu P
Citation: 
Blood Adv. 2021 Dec 14;5(23):4949-4962. doi: 10.1182/bloodadvances.2020003969
Abstract: 
RUNX1 is essential for the generation of hematopoietic stem cells (HSCs). Runx1-null mouse embryos lack definitive hematopoiesis and die in mid-gestation. However, although zebrafish embryos with a runx1 W84X mutation have defects in early definitive hematopoiesis, some runx1W84X/W84X embryos can develop to fertile adults with blood cells of multilineages, raising the possibility that HSCs can emerge without RUNX1. Here, using 3 new zebrafish runx1−/− lines, we uncovered the compensatory mechanism for runx1-independent hematopoiesis. We show that, in the absence of a functional runx1, a cd41-green fluorescent protein (GFP)+ population of hematopoietic precursors still emerge from the hemogenic endothelium and can colonize the hematopoietic tissues of the mutant embryos. Single-cell RNA sequencing of the cd41-GFP+ cells identified a set of runx1−/−-specific signature genes during hematopoiesis. Significantly, gata2b, which normally acts upstream of runx1 for the generation of HSCs, was increased in the cd41-GFP+ cells in runx1−/− embryos. Interestingly, genetic inactivation of both gata2b and its paralog gata2a did not affect hematopoiesis. However, knocking out runx1 and any 3 of the 4 alleles of gata2a and gata2b abolished definitive hematopoiesis. Gata2 expression was also upregulated in hematopoietic cells in Runx1−/− mice, suggesting the compensatory mechanism is conserved. Our findings indicate that RUNX1 and GATA2 serve redundant roles for HSC production, acting as each other’s safeguard.
Epub: 
Not Epub
Organism or Cell Type: 
zebrafish
Delivery Method: 
microinjection