The differentiation of hematopoietic stem cells (HSCs) is tightly controlled to ensure a proper balance between myeloid and lymphoid cell output. GATA2 is a pivotal hematopoietic transcription factor required for generation and maintenance of HSCs. GATA2 is expressed throughout development, but because of early embryonic lethality in mice, its role during adult hematopoiesis is incompletely understood. Zebrafish contains 2 orthologs of GATA2: Gata2a and Gata2b, which are expressed in different cell types. We show that the mammalian functions of GATA2 are split between these orthologs. Gata2bdeficient zebrafish have a reduction in embryonic definitive hematopoietic stem and progenitor cell (HSPC) numbers, but are viable. This allows us to uniquely study the role of GATA2 in adult hematopoiesis. gata2b mutants have impaired myeloid lineage differentiation. Interestingly, this defect arises not in granulocyte-monocyte progenitors, but in HSPCs. Gata2b-deficient HSPCs showed impaired progression of the myeloid transcriptional program, concomitant with increased coexpression of lymphoid genes. This resulted in a decrease in myeloid-programmed progenitors and a relative increase in lymphoid-programmed progenitors. This shift in the lineage output could function as an escape mechanism to avoid a block in lineage differentiation. Our study helps to deconstruct the functions of GATA2 during hematopoiesis and shows that lineage differentiation flows toward a lymphoid lineage in the absence of Gata2b.
|Number of pages||14|
|Early online date||26 Jun 2021|
|Publication status||Published - 13 Jul 2021|
Bibliographical noteFunding Information:
The authors thank members of the E.d.P., I.P.T., Raaijmakers, and Schneider-Kramann laboratories for helpful discussions; Tom Cupe-do (Erasmus MC) and Elaine Dzierzak (University of Edinburgh) for careful reading of the manuscript; and the Experimental Animal Facility of Erasmus MC for animal husbandry and the Erasmus Optical Imaging Center for confocal microscopy services. The visual abstract was created with BioRender.com. This research was supported by the European Hematology Association (junior nonclinical research fellowship) (E.d.P.), the Dutch Cancer Foundation/Alpe d’HuZes (SK10321) (E.d.P.), the British Heart Foundation (BHF IBSR fellowship FS/13/50/30436) (R.M. and C.B.M.), the Wellcome Trust (PhD scholarship #WT102345/Z/13/ Z) (T.D.), the Daniel den Hoed Foundation for support of the Cancer Genome Editing Center (I.P.T.), and the Josephine Nefkens Foundation for purchase of the Chromium (103 Genomics) (I.P.T.).
© 2021 by The American Society of Hematology.
ASJC Scopus subject areas