Roles of Disrupted-In-Schizophrenia 1-Interacting Protein Girdin in Postnatal Development of the Dentate Gyrus
Roles of Disrupted-In-Schizophrenia 1-Interacting Protein Girdin in Postnatal Development of the Dentate Gyrus
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DOI：
10.1016/j.neuron.2009.08.015
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发表时间：
2009-09-24
期刊：
影响因子：
16.2
通讯作者：
Takahashi, Masahide
中科院分区：
文献类型：
--
作者：
Enomoto, Atsushi;Asai, Naoya;Takahashi, Masahide
DISC1是一种主要精神疾病的易感基因，在哺乳动物大脑发育过程中调节神经元的迁移和分化。尽管DISC1在出生后齿状回（DG）神经发生中的作用最近被发现，但尚不清楚DISC1及其相互作用蛋白如何控制齿状颗粒细胞（DGCs）的迁移、定位和分化。在这里，我们报道DISC1与肌动蛋白结合蛋白girdin相互作用以调节轴突发育。girin缺乏的新生小鼠的DGCs表现出海马角氨区轴突发芽的缺陷。Girdin缺乏、RNA干扰介导的敲低和DISC1/ Girdin相互作用的抑制导致DGCs的过度迁移和错误定位，从而导致DGCs的严重细胞结构破坏。这些发现确定了girdin是DG出生后发育的内在因素，并提供了DISC1/girdin相互作用在DG出生后神经发生中的关键作用的见解。
Disrupted-in-Schizophrenia 1 (DISC1), a susceptibility gene for major psychiatric disorders, regulates neuronal migration and differentiation during mammalian brain development. Although roles for DISC1 in postnatal neurogenesis in the dentate gyrus (DG) have recently emerged, it is not known how DISC1 and its interacting proteins govern the migration, positioning, and differentiation of dentate granule cells (DGCs). Here, we report that DISC1 interacts with the actin-binding protein girdin to regulate axonal development. DGCs in girdin-deficient neonatal mice exhibit deficits in axonal sprouting in the cornu ammonis 3 region of the hippocampus.' Girdin deficiency, RNA interference-mediated knockdown, and inhibition of the DISC1/girdin interaction lead to overextended migration and mispositioning of the DGCs resulting in profound cytoarchitectural disorganization of the DG. These findings identify girdin as an intrinsic factor in postnatal development of the DG and provide insights into the critical role of the DISC1/girdin interaction in postnatal neurogenesis in the DG.