State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
Blood. 2014 Sep 4;124(10):1578-85. doi: 10.1182/blood-2013-11-541391. Epub 2014 Jul 8.
Nuclear receptor corepressors (Ncors) are important for developmental and homeostatic processes in vertebrates, which exert transcriptional repression by coordinating with histone deacetylases. However, little is known about their roles in definitive hematopoiesis. In this study, we show that in zebrafish, ncor2 is required for hematopoietic stem cell (HSC) development by repressing fos-vegfd signaling. ncor2 is specifically expressed in the aorta-gonad-mesonephros (AGM) region in zebrafish embryos. ncor2 deficiency reduced the population of HSCs in both the AGM region and T cells in the thymus. Mechanistically, ncor2 knockdown upregulated fos transcription by modulating the acetylation level in the fos promoter region, which then enhanced Vegfd signaling. Consequently, the augmented Vegfd signaling induced Notch signaling to promote the arterial endothelial fate, therefore, possibly repressing the hemogenic endothelial specification, which is a prerequisite for HSC emergence. Thus, our findings identify a novel regulatory mechanism for Ncor2 through Fos-Vegfd-Notch signaling cascade during HSC development in zebrafish embryos.
核受体辅抑制因子（Ncors）在脊椎动物的发育和动态平衡过程中非常重要，它们通过与组蛋白去乙酰化酶协调来发挥转录抑制作用。然而，关于它们在定型造血中的作用知之甚少。在这项研究中，我们表明在斑马鱼中，ncor2 通过抑制 fos-vegfd 信号来抑制造血干细胞（HSC）的发育。ncor2 在斑马鱼胚胎的主动脉-性腺-中肾（AGM）区域特异性表达。ncor2 缺失减少了 AGM 区域和胸腺中 T 细胞中的 HSC 群体。在机制上，ncor2 敲低通过调节 fos 启动子区域的乙酰化水平而上调 fos 转录，从而增强 Vegfd 信号。结果，增强的 Vegfd 信号诱导 Notch 信号促进动脉内皮命运，因此可能抑制造血内皮的特异性，这是 HSC 出现的前提。因此，我们的研究结果确定了一种通过 Fos-Vegfd-Notch 信号级联在斑马鱼胚胎 HSC 发育过程中对 Ncor2 进行调控的新机制。
