据两篇发表于9月24日Neuron的研究报告，科学家现在可以对一种导致严重精神衰弱疾病的基因有了更深入的了解。破坏DISC1基因(disrupted-in-schizophrenia 1)对海马体(hippocampus)中神经元的发育和迁移有重要影响，海马体是大脑中负责学习和记忆的区域，海马体异常或可能导致精神分裂症。
在第一份研究报告中，Enomoto等人发现DISC1可与肌动蛋白结合蛋白Girdin共同调节神经元轴突的形成。之前有研究表明Girdin是AKT的底物，与正常细胞结构的形成相关。对新生小鼠齿状回(dentate gyrus)缺失Girdin蛋白的细胞的研究表明，小鼠神经细胞不能形成轴突。而且，如果抑制DISC1/Girdin之间的相互作用将导致神经细胞在发育过程中出现异常迁移和错误定位。
在另一份研究中，约翰霍普金斯大学的Guo-li Ming等人发现，在成年人海马体新形成的神经元中抑制DISC1基因表达，将导致AKT过度活跃，而AKT基因是一种与精神分裂症相关的基因。进一步研究表明，抑制DISC1基因或基因改良AKT信号所导致的神经细胞发育异常，可以通过哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)进行改善。
结合上述两份研究发现，都说明了破坏DISC1基因表达将导致新生神经元发生错误的迁移和定位，并最终导致海马体神经细胞出现病理性混乱。（生物谷Bioon.com）
生物谷推荐原始出处：
Neuron, Volume 63, Issue 6, 24 September 2009 doi:10.1016/j.neuron.2009.08.015
Roles of Disrupted-In-Schizophrenia 1-Interacting Protein Girdin in Postnatal Development of the Dentate Gyrus
Atsushi Enomoto1, 4, 11, , , Naoya Asai1, 11, Takashi Namba5, 6, 11, Yun Wang1, 11, Takuya Kato1, Motoki Tanaka7, Hitoshi Tatsumi2, Shinichiro Taya3, 8, Daisuke Tsuboi3, 8, Keisuke Kuroda3, 8, Naoko Kaneko9, Kazunobu Sawamoto9, Rieko Miyamoto1, Mayumi Jijiwa1, Yoshiki Murakumo1, Masahiro Sokabe2, 7, Tatsunori Seki6, 10, Kozo Kaibuchi3, 8 and Masahide Takahashi1, ,
1 Department of Pathology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
2 Department of Physiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
3 Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
4 Institute for Advanced Research, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan
5 Department of Neurochemistry, National Institute of Neuroscience, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187-8502, Japan
6 Department of Anatomy, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo, Tokyo 113-8421, Japan
7 International Cooperative Research Project/Solution Oriented Research for Science and Technology, Cell Mechanosensing, Japan Science and Technology Agency, Nagoya 466-8550, Japan
8 Core Research for Evolutionary Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan
9 Department of Developmental and Regenerative Biology, Institute of Molecular Medicine, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan
10 Division of Developmental Neuroscience, Center for Translational and Advanced Animal Research, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan
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.
Neuron, Volume 63, Issue 6, 24 September 2009 doi:10.1016/j.neuron.2009.08.008
DISC1 Regulates New Neuron Development in the Adult Brain via Modulation of AKT-mTOR Signaling through KIAA1212
Ju Young Kim1, 2, 5, Xin Duan1, 2, 3, 5, Cindy Y. Liu1, 2, Mi-Hyeon Jang1, 2, Junjie U. Guo1, 3, Nattapol Pow-anpongkul1, 2, Eunchai Kang1, 4, Hongjun Song1, 2, 3, 4 and Guo-li Ming1, 2, 3, ,
1 Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
2 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
3 The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
4 Pre-doctoral Training Program in Human Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Disrupted-in-schizophrenia 1 (DISC1), a susceptibility gene for major mental illnesses, regulates multiple aspects of embryonic and adult neurogenesis. Here, we show that DISC1 suppression in newborn neurons of the adult hippocampus leads to overactivated signaling of AKT, another schizophrenia susceptibility gene. Mechanistically, DISC1 directly interacts with KIAA1212, an AKT binding partner that enhances AKT signaling in the absence of DISC1, and DISC1 binding to KIAA1212 prevents AKT activation in vitro. Functionally, multiple genetic manipulations to enhance AKT signaling in adult-born neurons in vivo exhibit similar defects as DISC1 suppression in neuronal development that can be rescued by pharmacological inhibition of mammalian target of rapamycin (mTOR), an AKT downstream effector. Our study identifies the AKT-mTOR signaling pathway as a critical DISC1 target in regulating neuronal development and provides a framework for understanding how multiple susceptibility genes may functionally converge onto a common pathway in contributing to the etiology of certain psychiatric disorders.
