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The orphan nuclear receptor Nurr1 restricts the proliferation of haematopoietic stem cells

Nature Cell Biology volume 12, pages 1213–1219 (2010)Cite this article

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Abstract

Successful haematopoiesis requires long-term retention of haematopoietic stem cells (HSCs) in a quiescent state. The transcriptional regulation of stem cell quiescence, especially by factors with specific functions in HSCs, is only beginning to be understood. Here, we demonstrate that Nurr1, a nuclear receptor transcription factor, has such a regulatory role. Overexpression of Nurr1 drives early haematopoietic progenitors into quiescence. When stem cells overexpressing Nurr1 are transplanted into lethally irradiated mice, they localize to the bone marrow, but do not contribute to regeneration of the blood system. Furthermore, the loss of only one allele of Nurr1 is sufficient to induce HSCs to enter the cell cycle and proliferate. Molecular analysis revealed an association between Nurr1 overexpression and upregulation of the cell-cycle inhibitor p18 (also known as INK4C), suggesting a mechanism by which Nurr1 could regulate HSC quiescence. Our findings provide critical insight into the transcriptional control mechanisms that determine whether HSCs remain dormant or enter the cell cycle and begin to proliferate.

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Figure 1: Nurr1 is highly expressed in quiescent HSCs (Hoechst 33342 side-population cells that are also c-Kit+, Sca1+ and Lin−; SP-KSL) and its overexpression in 32D cells results in a proliferative block.
Figure 2: Overexpression of Nurr1 in bone-marrow cells reversibly blocks proliferation.
Figure 3: Nurr1 overexpression leads to reduced cell-cycle proliferation.
Figure 4: Dose effect of Nurr1 on expression of cell-cycle inhibitors and rescue of the Nurr1 phenotype by p18 expression.

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Acknowledgements

We thank N. Boles, E. J. Dettman, and J. Gilbert for helpful discussion and suggestions, and T. Perlmann for comments on the manuscript. This work was supported by NIH grants DK58192, CA111411, CA126752, EB005173 and AG034451, as well as Ellison Foundation grant AG-SS178706, and the Dan L. Duncan Cancer Center. T. Cheng provided p18-null mice. We also thank S. Watowich for 32D cells.

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Authors and Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, 77030, TX, USA

    Olga Sirin & Margaret A. Goodell

  2. Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, 77030, TX, USA

    Olga Sirin, Georgi L. Lukov, Rui Mao & Margaret A. Goodell

  3. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, 77030, TX, USA

    Orla M. Conneely & Margaret A. Goodell

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  1. Olga Sirin
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Contributions

This study was developed and designed by O.S., who also performed the experiments and co-wrote the manuscript. G.L.L. and R.M. helped carry out the experiments. O.M.C. provided Nurr1−/− mice and discussion. M.A.G. designed experiments and co-wrote the manuscript.

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Correspondence to Margaret A. Goodell.

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Sirin, O., Lukov, G., Mao, R. et al. The orphan nuclear receptor Nurr1 restricts the proliferation of haematopoietic stem cells. Nat Cell Biol 12, 1213–1219 (2010). https://doi.org/10.1038/ncb2125

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