Glucocorticoid-related molecular signaling pathways regulating hippocampal neurogenesis.
Glucocorticoid-related molecular signaling pathways regulating hippocampal neurogenesis.
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DOI：
10.1038/npp.2012.253
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发表时间：
2013-04
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影响因子：
--
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应激和糖皮质激素调节海马神经发生，但其作用的分子机制尚不清楚。因此，我们研究了在永生化的人类海马祖细胞系中，皮质醇对增殖、神经元分化和星形胶质形成的影响的分子信号通路。此外，我们还检测了胎儿期应激大鼠海马区激活的分子信号通路，其特征是成年后糖皮质激素水平持续升高。在人类海马祖细胞中，我们发现低浓度的皮质醇(100 NM)促进了增殖(+16%)，减少了向微管相关蛋白2(−)阳性神经元(−24%)和双重皮质素(Dcx)阳性神经母细胞(−21%)的神经发生，并增加了向S100β阳性星形胶质细胞的分化(+23%)。这些效应依赖于盐皮质激素受体(MR)，因为它们被MR拮抗剂螺内酯取消，并被MR激动剂醛固酮模拟。相反，高浓度皮质醇(100 μM)抑制细胞增殖(−17%)和分化为MAP2阳性神经元(−22%)和Dcx阳性神经母细胞(−27%)，但不影响星形胶质细胞的形成。这些效应依赖于糖皮质激素受体，被糖皮质激素受体拮抗剂RU486阻断，并被糖皮质激素受体激动剂地塞米松模拟。基因表达芯片和通路分析表明，低浓度皮质醇促进Notch/Hes信号转导，高浓度抑制转化生长因子β-Smad2/3信号转导，两种浓度均抑制Hedgehog信号转导。从机制上讲，我们证明Hedgehog信号的减少确实是皮质醇诱导的神经元分化减少的关键因素。相应地，转化生长因子β-Smad2/3和Hedgehog信号通路也在胎儿期应激高糖皮质激素水平的成年大鼠的海马区受到抑制。总之，我们的数据显示了糖皮质激素在体外、在人海马祖细胞中以及在体内、在大鼠海马区受应激调控的新的分子信号通路。
Stress and glucocorticoid hormones regulate hippocampal neurogenesis, but the molecular mechanisms underlying their effects are unknown. We, therefore, investigated the molecular signaling pathways mediating the effects of cortisol on proliferation, neuronal differentiation, and astrogliogenesis, in an immortalized human hippocampal progenitor cell line. In addition, we examined the molecular signaling pathways activated in the hippocampus of prenatally stressed rats, characterized by persistently elevated glucocorticoid levels in adulthood. In human hippocampal progenitor cells, we found that low concentrations of cortisol (100 nM) increased proliferation (+16%), decreased neurogenesis into microtubule-associated protein 2 (MAP2)-positive neurons (−24%) and doublecortin (Dcx)-positive neuroblasts (−21%), and increased differentiation into S100β-positive astrocytes (+23%). These effects were dependent on the mineralocorticoid receptor (MR) as they were abolished by the MR antagonist, spironolactone, and mimicked by the MR-agonist, aldosterone. In contrast, high concentrations of cortisol (100 μM) decreased proliferation (−17%) and neuronal differentiation into MAP2-positive neurons (−22%) and into Dcx-positive neuroblasts (−27%), without regulating astrogliogenesis. These effects were dependent on the glucocorticoid receptor (GR), blocked by the GR antagonist RU486, and mimicked by the GR-agonist, dexamethasone. Gene expression microarray and pathway analysis showed that the low concentration of cortisol enhances Notch/Hes-signaling, the high concentration inhibits TGFβ-SMAD2/3-signaling, and both concentrations inhibit Hedgehog signaling. Mechanistically, we show that reduced Hedgehog signaling indeed critically contributes to the cortisol-induced reduction in neuronal differentiation. Accordingly, TGFβ-SMAD2/3 and Hedgehog signaling were also inhibited in the hippocampus of adult prenatally stressed rats with high glucocorticoid levels. In conclusion, our data demonstrate novel molecular signaling pathways that are regulated by glucocorticoids in vitro, in human hippocampal progenitor cells, and by stress in vivo, in the rat hippocampus.
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影响因子：
11
作者：
Anacker, C.;Zunszain, P. A.;Cattaneo, A.;Carvalho, L. A.;Garabedian, M. J.;Thuret, S.;Price, J.;Pariante, C. M.
通讯作者：
Pariante, C. M.
影响因子：
3.7
作者：
Chang, Ya-Ting;Chen, Yi-Chieh;Kuo, Yu-Min
通讯作者：
Kuo, Yu-Min
影响因子：
3.5
作者：
Datson, Nicole A.;Speksnijder, Niels;Lucassen, Paul J.
通讯作者：
Lucassen, Paul J.
影响因子：
3.7
作者：
Anacker, Christoph;Zunszain, Patricia A.;Carvalho, Livia A.;Pariante, Carmine M.
通讯作者：
Pariante, Carmine M.
DOI：
10.1007/s00406-009-0036-y
发表时间：
2009-12
影响因子：
4.7
作者：
Kronenberg G;Kirste I;Inta D;Chourbaji S;Heuser I;Endres M;Gass P
通讯作者：
Gass P