據(jù)兩篇發(fā)表于9月24日Neuron的研究報(bào)告，科學(xué)家現(xiàn)在可以對(duì)一種導(dǎo)致嚴(yán)重精神衰弱疾病的基因有了更深入的了解。破壞DISC1基因(disrupted-in-schizophrenia 1)對(duì)海馬體(hippocampus)中神經(jīng)元的發(fā)育和遷移有重要影響,，海馬體是大腦中負(fù)責(zé)學(xué)習(xí)和記憶的區(qū)域，海馬體異?；蚩赡軐?dǎo)致精神分裂癥,。

在第一份研究報(bào)告中，Enomoto等人發(fā)現(xiàn)DISC1可與肌動(dòng)蛋白結(jié)合蛋白Girdin共同調(diào)節(jié)神經(jīng)元軸突的形成,。之前有研究表明Girdin是AKT的底物,，與正常細(xì)胞結(jié)構(gòu)的形成相關(guān)。對(duì)新生小鼠齒狀回(dentate  gyrus)缺失Girdin蛋白的細(xì)胞的研究表明,，小鼠神經(jīng)細(xì)胞不能形成軸突,。而且，如果抑制DISC1/Girdin之間的相互作用將導(dǎo)致神經(jīng)細(xì)胞在發(fā)育過(guò)程中出現(xiàn)異常遷移和錯(cuò)誤定位,。

在另一份研究中,，約翰霍普金斯大學(xué)的Guo-li  Ming等人發(fā)現(xiàn)，在成年人海馬體新形成的神經(jīng)元中抑制DISC1基因表達(dá),，將導(dǎo)致AKT過(guò)度活躍,，而AKT基因是一種與精神分裂癥相關(guān)的基因。進(jìn)一步研究表明,，抑制DISC1基因或基因改良AKT信號(hào)所導(dǎo)致的神經(jīng)細(xì)胞發(fā)育異常,，可以通過(guò)哺乳動(dòng)物雷帕霉素靶蛋白(mammalian target of rapamycin,mTOR)進(jìn)行改善。

結(jié)合上述兩份研究發(fā)現(xiàn),，都說(shuō)明了破壞DISC1基因表達(dá)將導(dǎo)致新生神經(jīng)元發(fā)生錯(cuò)誤的遷移和定位,，并最終導(dǎo)致海馬體神經(jīng)細(xì)胞出現(xiàn)病理性混亂。（生物谷Bioon.com）

生物谷推薦原始出處：

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.