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

Abstract

Successful hematopoiesis requires long-term retention of the quiescent state of hematopoietic stem cells (HSCs). 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. Enforced expression of Nurr1 drives early hematopoietic progenitors into quiescence. When stem cells overexpressing Nurr1 are transplanted into lethally irradiated mice, they home 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, 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.