The transcription factor GATA-3 is expressed and required for differentiation and function throughout the T lymphocyte lineage. Despite evidence it may also be expressed in multipotent hematopoietic stem cells (HSCs), any role for GATA-3 in these cells has remained unclear. Here we found GATA-3 was in the cytoplasm in quiescent long-term stem cells from steady-state bone marrow but relocated to the nucleus when HSCs cycled. Relocation depended on signaling via the mitogen-activated protein kinase p38 and was associated with a diminished capacity for long-term reconstitution after transfer into irradiated mice. Deletion of Gata3 enhanced the repopulating capacity and augmented the self-renewal of long-term HSCs in cell-autonomous fashion without affecting the cell cycle. Our observations position GATA-3 as a regulator of the balance between self-renewal and differentiation in HSCs that acts downstream of the p38 signaling pathway.
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We thank F. Melchers (Max Planck Institute for Infection Biology) for conditioned medium from transduced mouse cells that produce IL-7; P.A. Penttilä for assistance with flow cytometry and M.F. Monroy for help with animal procedures. Supported by the Terry Fox Foundation, the Canadian Cancer Research Institute, the Canadian Institutes of Health Research, the Stem Cell Network, the Fondation de France (C.F.), the Fondation pour la Recherche Médicale (C.F.), the McEwen Centre for Regenerative Medicine, the Princess Margaret Hospital Foundation, the Campbell Family Institute for Cancer Research and the Ontario Ministry of Health and Long Term Care. The views expressed do not necessarily reflect those of the Ontario Ministry of Health and Long Term Care.
The authors declare no competing financial interests.
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Frelin, C., Herrington, R., Janmohamed, S. et al. GATA-3 regulates the self-renewal of long-term hematopoietic stem cells. Nat Immunol 14, 1037–1044 (2013). https://doi.org/10.1038/ni.2692
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