Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Nat Cell Biol. 2010 Dec;12(12):1213-9. doi: 10.1038/ncb2125. Epub 2010 Nov 14.
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.
成功的造血需要长期保持造血干细胞（HSCs）处于静止状态。干细胞静止的转录调控，特别是具有 HSCs 特定功能的因子的转录调控，才刚刚开始被理解。在这里，我们证明了核受体转录因子 Nurr1 具有这种调节作用。Nurr1 的过表达将早期造血祖细胞驱入静止状态。当过表达 Nurr1 的干细胞被移植到致死性辐射的小鼠中时，它们定位于骨髓，但不会促进血液系统的再生。此外，Nurr1 的一个等位基因的缺失足以诱导 HSCs 进入细胞周期并增殖。分子分析显示，Nurr1 的过表达与细胞周期抑制剂 p18（也称为 INK4C）的上调之间存在关联，这表明了 Nurr1 可能调节 HSC 静止的一种机制。我们的发现为决定 HSCs 是保持休眠还是进入细胞周期并开始增殖的转录控制机制提供了重要的见解。
