Essential role for Gata2 in modulating lineage output from hematopoietic stem cells in zebrafish

Emanuele Gioacchino, Cansu Koyunlar, Joke Zink, Hans de Looper, Madelon de Jong, Tomasz Dobrzycki, Christopher B. Mahony, Remco Hoogenboezem, Dennis Bosch, Paulina M.H. van Strien, Martin E. van Royen, Pim J. French, Eric Bindels, Kirsten J. Gussinklo, Rui Monteiro, Ivo P. Touw, Emma de Pater

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Abstract

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.

Original languageEnglish
Pages (from-to)2687-2700
Number of pages14
JournalBlood Advances
Volume5
Issue number13
Early online date26 Jun 2021
DOIs
Publication statusPublished - 13 Jul 2021

ASJC Scopus subject areas

  • Hematology

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