Duan Xin, Chang Jay H, Ge Shaoyu, Faulkner Regina L, Kim Ju Young, Kitabatake Yasuji, Liu Xiao-bo, Yang Chih-Hao, Jordan J Dedrick, Ma Dengke K, Liu Cindy Y, Ganesan Sundar, Cheng Hwai-Jong, Ming Guo-li, Lu Bai, Song Hongjun
Institute for Cell Engineering, Johns Hopkins University School of Medicine, 733 N. Broadway, Baltimore, MD 21205, USA.
Cell. 2007 Sep 21;130(6):1146-58. doi: 10.1016/j.cell.2007.07.010. Epub 2007 Sep 6.
Adult neurogenesis occurs throughout life in discrete regions of the adult mammalian brain. Little is known about the mechanism governing the sequential developmental process that leads to integration of new neurons from adult neural stem cells into the existing circuitry. Here, we investigated roles of Disrupted-In-Schizophrenia 1 (DISC1), a schizophrenia susceptibility gene, in adult hippocampal neurogenesis. Unexpectedly, downregulation of DISC1 leads to accelerated neuronal integration, resulting in aberrant morphological development and mispositioning of new dentate granule cells in a cell-autonomous fashion. Functionally, newborn neurons with DISC1 knockdown exhibit enhanced excitability and accelerated dendritic development and synapse formation. Furthermore, DISC1 cooperates with its binding partner NDEL1 in regulating adult neurogenesis. Taken together, our study identifies DISC1 as a key regulator that orchestrates the tempo of functional neuronal integration in the adult brain and demonstrates essential roles of a susceptibility gene for major mental illness in neuronal development, including adult neurogenesis.
成体神经发生在成年哺乳动物大脑的离散区域终生存在。对于控制成年神经干细胞产生的新神经元整合到现有神经回路中的连续发育过程的机制，我们知之甚少。在此，我们研究了精神分裂症易感基因精神分裂症1缺失基因（DISC1）在成年海马神经发生中的作用。出乎意料的是，DISC1的下调导致神经元整合加速，以细胞自主方式导致新的齿状颗粒细胞形态发育异常和位置错误。在功能上，敲低DISC1的新生神经元表现出增强的兴奋性、加速的树突发育和突触形成。此外，DISC1与其结合伴侣NDEL1协同调节成年神经发生。综上所述，我们的研究确定DISC1是协调成年大脑中功能性神经元整合节奏的关键调节因子，并证明了一种主要精神疾病易感基因在包括成体神经发生在内的神经元发育中的重要作用。
