Blocked inhibitory serine-phosphorylation of glycogen synthase kinase-3alpha/beta impairs in vivo neural precursor cell proliferation.
Blocked inhibitory serine-phosphorylation of glycogen synthase kinase-3alpha/beta impairs in vivo neural precursor cell proliferation.
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DOI：
10.1016/j.biopsych.2009.04.015
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发表时间：
2009-09-01
影响因子：
10.6
通讯作者：
Jope, Richard S.
中科院分区：
文献类型：
--
作者：
Eom, Tae-Yeon;Jope, Richard S.
成人神经发生增强了神经元的可塑性，神经发生缺陷可能导致情绪障碍和精神分裂症，并阻碍治疗反应。由于这些疾病可能与糖原合成酶激酶3 （GSK3）控制不充分有关，我们测试了GSK3抑制丝氨酸磷酸化阻断是否会损害神经发生。通过齿状回BrdU标记GSK3alpha/beta21A/21A/9A/9A敲入具有丝氨酸-丙氨酸突变的小鼠的神经前体细胞（NPC）增殖，以阻断GSK3的抑制丝氨酸磷酸化，而其仍在生理范围内，因为GSK3没有过表达。与野生型小鼠相比，GSK3敲入小鼠体内的神经发生损伤高达40%。受损的神经发生可能是由于GSK3对npc或周围调节npc的细胞的影响。GSK3敲入基因小鼠与野生型小鼠的NPC体外增殖相同，提示GSK3敲入基因小鼠体内缺乏外部支持的NPC增殖。对两种促进神经发生的神经营养因子的测量显示，GSK3敲入小鼠的海马血管内皮生长因子比野生型小鼠少，而脑源性生长因子则没有，这加强了GSK3敲入小鼠中环境支持不足可能导致神经发生受损的可能性。体内慢性联合给药锂和氟西汀分别增加了野生型GSK3的丝氨酸抑制磷酸化，增加了野生型小鼠的鼻咽癌增殖，但没有GSK3敲入小鼠。阻断GSK3的抑制控制损害了神经发生和治疗药物刺激神经发生的能力，可能是由于缺乏支持神经发生的环境因素，这可能导致精神疾病和对治疗药物的反应。
Adult neurogenesis augments neuronal plasticity, and deficient neurogenesis may contribute to mood disorders and schizophrenia and impede treatment responses. Since these diseases may be associated with inadequately controlled glycogen synthase kinase-3 (GSK3), we tested if blocked inhibitory serine-phosphorylation of GSK3 impairs neurogenesis. Neural precursor cell (NPC) proliferation was measured by dentate gyrus BrdU labeling in GSK3alpha/beta21A/21A/9A/9A knockin mice with serine-to-alanine mutations to block inhibitory serine-phosphorylation of GSK3 while it remains within the physiological range, since GSK3 is not overexpressed. There was a drastic 40% impairment in neurogenesis in vivo in GSK3 knockin mice compared with wild-type mice. Impaired neurogenesis could be due to effects of GSK3 in NPCs or in surrounding cells that modulate NPCs. In vitro proliferation was equivalent for NPCs from GSK3 knockin and wild-type mice, suggesting an in vivo deficiency in GSK3 knockin mice of external support for NPC proliferation. Measurements of two neurotrophins that promote neurogenesis demonstrated less hippocampal vascular endothelial growth factor, but not brain-derived growth factor, in GSK3 knockin mice than wild-type mice, reinforcing the possibility that insufficient environmental support in GSK3 knockin mice may contribute to impaired neurogenesis. In vivo chronic co-administration of lithium and fluoxetine, which each increase inhibitory serine-phosphorylation of wild-type GSK3, increased NPC proliferation in wild-type, but not GSK3 knockin, mice. Blocked inhibitory control of GSK3 impaired neurogenesis and the capacity of therapeutic drugs to stimulate neurogenesis, likely through deficient environmental factors that support neurogenesis, which may contribute to psychiatric diseases and responses to therapeutic drugs.
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影响因子：
4.7
作者：
Chen, G;Rajkowska, G;Manji, HK
通讯作者：
Manji, HK
DOI：
10.1073/pnas.120552597
发表时间：
2000-06-20
影响因子：
11.1
作者：
Eisch, AJ;Barrot, M;Nestler, EJ
通讯作者：
Nestler, EJ
影响因子：
10.6
作者：
Duman, RS;Malberg, J;D'Sa, C
通讯作者：
D'Sa, C
DOI：
10.1073/pnas.182296499
发表时间：
2002-09-03
影响因子：
11.1
作者：
Jin, KL;Zhu, YH;Greenberg, DA
通讯作者：
Greenberg, DA
影响因子：
2.9
作者：
Balu, Darrick T.;Hoshaw, Brian A.;Lucki, Irwin
通讯作者：
Lucki, Irwin