Stress, Psychiatry and Immunology Laboratory, Department of Psychological Medicine, Institute of Psychiatry, King's College London, London SE5 9NU, United Kingdom.
Proc Natl Acad Sci U S A. 2013 May 21;110(21):8708-13. doi: 10.1073/pnas.1300886110. Epub 2013 May 6.
Stress and glucocorticoid hormones regulate hippocampal neurogenesis, but the molecular mechanisms mediating these effects are poorly understood. Here we identify the glucocorticoid receptor (GR) target gene, serum- and glucocorticoid-inducible kinase 1 (SGK1), as one such mechanism. Using a human hippocampal progenitor cell line, we found that a small molecule inhibitor for SGK1, GSK650394, counteracted the cortisol-induced reduction in neurogenesis. Moreover, gene expression and pathway analysis showed that inhibition of the neurogenic Hedgehog pathway by cortisol was SGK1-dependent. SGK1 also potentiated and maintained GR activation in the presence of cortisol, and even after cortisol withdrawal, by increasing GR phosphorylation and GR nuclear translocation. Experiments combining the inhibitor for SGK1, GSK650394, with the GR antagonist, RU486, demonstrated that SGK1 was involved in the cortisol-induced reduction in progenitor proliferation both downstream of GR, by regulating relevant target genes, and upstream of GR, by increasing GR function. Corroborating the relevance of these findings in clinical and rodent settings, we also observed a significant increase of SGK1 mRNA in peripheral blood of drug-free depressed patients, as well as in the hippocampus of rats subjected to either unpredictable chronic mild stress or prenatal stress. Our findings identify SGK1 as a mediator for the effects of cortisol on neurogenesis and GR function, with particular relevance to stress and depression.
应激和糖皮质激素调节海马神经发生，但介导这些效应的分子机制仍不清楚。在这里，我们确定了糖皮质激素受体（GR）的靶基因，即血清和糖皮质激素诱导的激酶 1（SGK1），作为其中的一种机制。使用人海马祖细胞系，我们发现 SGK1 的小分子抑制剂 GSK650394 可拮抗皮质醇诱导的神经发生减少。此外，基因表达和通路分析表明，皮质醇诱导的神经发生 Hedgehog 通路的抑制作用依赖于 SGK1。SGK1 还通过增加 GR 磷酸化和 GR 核易位，增强并维持皮质醇存在时的 GR 激活，甚至在皮质醇撤出后也是如此。结合 SGK1 的抑制剂 GSK650394 和 GR 拮抗剂 RU486 的实验表明，SGK1 参与了皮质醇诱导的祖细胞增殖减少，这既可以通过调节相关靶基因在 GR 下游发挥作用，也可以通过增加 GR 功能在 GR 上游发挥作用。在临床和啮齿动物研究中，这些发现具有相关性，我们还观察到在未经药物治疗的抑郁患者的外周血中以及在经历不可预测的慢性轻度应激或产前应激的大鼠的海马体中，SGK1 mRNA 显著增加。我们的研究结果确定了 SGK1 作为皮质醇对神经发生和 GR 功能影响的中介物，特别是与应激和抑郁相关。
