Toll-like receptors modulate adult hippocampal neurogenesis
Toll-like receptors modulate adult hippocampal neurogenesis
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DOI：
10.1038/ncb1629
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发表时间：
2007-09-01
影响因子：
21.3
通讯作者：
Schwartz, Michal
中科院分区：
文献类型：
--
作者：
Rolls, Asya;Shechter, Ravid;Schwartz, Michal
神经发生——成人大脑中新神经元的形成——被认为是大脑在应对外在和内在变化时保持其终身可塑性的机制之一(1)。神经发生调控的机制在很大程度上是未知的。在这里，我们发现toll样受体（TLRs），一个高度保守的模式识别受体家族，参与果蝇的神经系统发育(2)和哺乳动物的先天免疫活动（3,4），调节成年海马神经发生。我们发现TLR2和TLR4存在于成人神经干/祖细胞（NPC）上，并且在体外和体内对NPC的增殖和分化具有不同的和相反的功能。小鼠的TLR2缺失会损害海马神经发生，而TLR4缺失会导致增殖和神经元分化增强。体外研究进一步表明，TLR2和TLR4直接调节npc的自我更新和细胞命运决定。NPCs上TLRs的激活是通过MyD88介导的，并诱导PKC α / β依赖性nf - κ B信号通路的激活。因此，我们的研究确定了tlr在成人神经发生中的作用，并强调了它们在细胞更新中的特定和多样化作用。
Neurogenesis-the formation of new neurons in the adult brain - is considered to be one of the mechanisms by which the brain maintains its lifelong plasticity in response to extrinsic and intrinsic changes(1). The mechanisms underlying the regulation of neurogenesis are largely unknown. Here, we show that Toll-like receptors (TLRs), a family of highly conserved pattern-recognizing receptors involved in neural system development in Drosophila(2) and innate immune activity in mammals(3,4), regulate adult hippocampal neurogenesis. We show that TLR2 and TLR4 are found on adult neural stem/progenitor cells (NPCs) and have distinct and opposing functions in NPC proliferation and differentiation both in vitro and in vivo. TLR2 deficiency in mice impaired hippocampal neurogenesis, whereas the absence of TLR4 resulted in enhanced proliferation and neuronal differentiation. In vitro studies further indicated that TLR2 and TLR4 directly modulated self-renewal and the cell-fate decision of NPCs. The activation of TLRs on the NPCs was mediated via MyD88 and induced PKC alpha/beta-dependent activation of the NF-kappa B signalling pathway. Thus, our study identified TLRs as players in adult neurogenesis and emphasizes their specified and diverse role in cell renewal.