d-Serine Regulates Proliferation and Neuronal Differentiation of Neural Stem Cells from Postnatal Mouse Forebrain
d-Serine Regulates Proliferation and Neuronal Differentiation of Neural Stem Cells from Postnatal Mouse Forebrain
复制标题
d-丝氨酸调节产后小鼠前脑神经干细胞的增殖和神经元分化
DOI：
10.1111/j.1755-5949.2011.00276.x
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发表时间：
2012-01-01
影响因子：
5.5
通讯作者：
Hu, Gang
中科院分区：
文献类型：
--
作者：
Huang, Xu;Kong, Hui;Hu, Gang
背景和目的：丝氨酸是N-甲基-d-天冬氨酸（NMdA）受体的内源性共激动剂，是哺乳动物脑内重要的神经胶质递质。D-丝氨酸已经显示出防止精神兴奋剂诱导的海马神经发生的减少。然而，d-丝氨酸调节神经发生的机制尚未完全确定。因此，本研究旨在探讨d-丝氨酸对原代培养的神经干细胞（NSCs）增殖、迁移和分化的影响。方法和结果：免疫组化显示神经干细胞表达d-丝氨酸和丝氨酸消旋酶（SR）。用d-氨基酸氧化酶（dAAO）降解内源性d-丝氨酸可显著抑制NSCs的增殖和神经元分化，但不影响NSCs的径向迁移。补充外源性d-丝氨酸不影响神经干细胞的增殖和迁移，但促进神经干细胞向神经元分化。此外，dAAO可抑制谷氨酸诱导的Ca 2+瞬变幅度，从而抑制糖原合成酶激酶3 β（GSK 3 β）、细胞外信号调节激酶1/2（ERK 1/2）和cAMP反应元件结合蛋白（CREB）的磷酸化。结论：我们的研究结果首次证明，神经干细胞可以合成d-丝氨酸，从而促进自身增殖和神经元分化，这可能为需要神经细胞补充的神经系统疾病，如神经退行性疾病和中风提供新的治疗策略。
Background and purpose: d-Serine, the endogenous co-agonist of N-methyl-d-aspartate (NMdA) receptors, has been recognized as an important gliotransmitter in the mammalian brain. d-serine has been shown to prevent psychostimulant-induced decrease in hippocampal neurogenesis. However, the mechanism whereby d-serine regulates neurogenesis has not been fully characterized. Therefore, this study was designed to investigate the impacts of d-serine on the proliferation, migration, and differentiation of primary cultured neural stem cells (NSCs). Methods and results: Immunohistochemistry analysis revealed NSCs expressed d-serine as well as serine racemase (SR). Degradation of endogenous d-serine with d-amino acid oxidase (dAAO) significantly inhibited the proliferation and neuronal differentiation of NSCs, but failed to affect their radial migration. Reversely, addition of exogenous d-serine did not affect the proliferation and migration of NSCs, but promoted NSC differentiation into neurons. Furthermore, dAAO could suppress the amplitude of glutamate-induced Ca2+ transient, and thereby, inhibited the phosphorylation of glycogen synthase kinase3 beta (GSK3 beta), extracellular signal-regulated kinases1/2 (ERK1/2), and cAMP-responsive element-binding protein (CREB). Conclusions: Our findings demonstrate for the first time that NSCs can synthesize d-serine and, thereby, promote themselves proliferation and neuronal differentiation, which may afford a novel therapeutic strategy for the neurological disorders that require nerve cell replenishment, such as neurodegenerative diseases and stroke.