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A correction to this article has been published: Purton et al., J. Exp. Med. 203 (6) 1615
Published online 8 May 2006 doi:10.1084/jem.20052105
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 5, 1283-1293
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ARTICLE

 RAR{gamma} is critical for maintaining a balance between hematopoietic stem cell self-renewal and differentiation

Louise E. Purton1, Sebastian Dworkin1, Gemma Haines Olsen1, Carl R. Walkley1,2, Stewart A. Fabb1, Steven J. Collins3, and Pierre Chambon4

1 Trescowthick Research Laboratories, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia
2 Department of Medicine, University of Melbourne, Fitzroy, Victoria 3065, Australia
3 Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109
4 Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/ULP/Collège de France, 67404 Illkirch Cedex, CU de Strasbourg, France

CORRESPONDENCE Louise E. Purton: lpurton{at}partners.org

Hematopoietic stem cells (HSCs) sustain lifelong production of all blood cell types through finely balanced divisions leading to self-renewal and differentiation. Although several genes influencing HSC self-renewal have been identified, to date no gene has been described that, when activated, enhances HSC self-renewal and, when activated, promotes HSC differentiation. We observe that the retinoic acid receptor (RAR){gamma} is selectively expressed in primitive hematopoietic precursors and that the bone marrow of RAR{gamma} knockout mice exhibit markedly reduced numbers of HSCs associated with increased numbers of more mature progenitor cells compared with wild-type mice. In contrast, RAR{alpha} is widely expressed in hematopoietic cells, but RAR{alpha} knockout mice do not exhibit any HSC or progenitor abnormalities. Primitive hematopoietic precursors overexpressing RAR{alpha} differentiate predominantly to granulocytes in short-term culture, whereas those overexpressing RAR{gamma} exhibit a much more undifferentiated phenotype. Furthermore, loss of RAR{gamma} abrogated the potentiating effects of all-trans retinoic acid on the maintenance of HSCs in ex vivo culture. Finally, pharmacological activation of RAR{gamma} ex vivo promotes HSC self-renewal, as demonstrated by serial transplant studies. We conclude that the RARs have distinct roles in hematopoiesis and that RAR{gamma} is a critical physiological and pharmacological regulator of the balance between HSC self-renewal and differentiation.

Abbreviations used: ATRA, all-trans retinoic acid; BMT, BM transplant; CFU-GEMM, CFU-granulocyte, erythrocyte, macrophage, megakaryocyte; CFU-S, CFU-spleen; CLP, common lymphoid progenitor; CMP, common myeloid progenitor; Hes1, hairy and enhancer of split 1; HSC, hematopoietic stem cell; LKS+, lineage-negative, c-kit–positive, Sca-1–positive cells; LKS–, lineage-negative, c-kit–positive, Sca-1–negative cells; RAR, retinoic acid receptor; RU, repopulating unit.

Louise E. Purton's present address is Center for Regenerative Medicine, Harvard Medical School, Harvard Stem Cell Institute, Massachusetts General Hospital, Boston, MA 02114.

Carl R. Walkley's present address is Pediatric Oncololgy and Department of Hematology-Oncology, Dana-Farber Cancer Institute and Children's Hospital, Harvard Medical School, Boston, MA 02115.


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