1. ¹Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA
2. ²Consolidated Research Institute for Advanced Science and Medical Care (ASMeW), Waseda University, Tokyo, Japan
3. ³Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan
4. ⁴Department of Biochemistry, Hokkaido University, Sapporo, Japan
5. ⁵Division of Insect Sciences, National Institute of Agrobiological Sciences, Tsukuba, Japan
6. ⁶Division of Neurosciences, Beckman Research Institute, City of Hope, CA, USA
7. ⁷Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
8. ⁸Clock Cell Biology Research Group, National Institute of Advanced Industrial Science and Technology, Tsukuba, Japan
9. ⁹Department of Molecular and Cellular Biochemistry, Center for Molecular Neurobiology, Ohio State University, Columbus, OH, USA

Correspondence: Dr A Sawa, Department of Psychiatry, Johns Hopkins School of Medicine, 600 North Wolfe St. CMSC 8-117, Baltimore, MD 21287, USA. E-mail: asawa1@jhmi.edu; Dr K Furukubo-Tokunaga, 1-1-1 Tennoudai, Tsukuba 305-8572, Japan. E-mail: tokunaga@sakura.cc.tsukuba.ac.jp

Received 26 August 2007; Revised 22 July 2008; Accepted 7 August 2008; Published online 2 September 2008.

Abstract

Disrupted-in-schizophrenia-1 (DISC1) is one of major susceptibility factors for a wide range of mental illnesses, including schizophrenia, bipolar disorder, major depression and autism spectrum conditions. DISC1 is located in several subcellular domains, such as the centrosome and the nucleus, and interacts with various proteins, including NudE-like (NUDEL/NDEL1) and activating transcription factor 4 (ATF4)/CREB2. Nevertheless, a role for DISC1 in vivo remains to be elucidated. Therefore, we have generated a Drosophila model for examining normal functions of DISC1 in living organisms. DISC1 transgenic flies with preferential accumulation of exogenous human DISC1 in the nucleus display disturbance in sleep homeostasis, which has been reportedly associated with CREB signaling/CRE-mediated gene transcription. Thus, in mammalian cells, we characterized nuclear DISC1, and identified a subset of nuclear DISC1 that colocalizes with the promyelocytic leukemia (PML) bodies, a nuclear compartment for gene transcription. Furthermore, we identified three functional cis-elements that regulate the nuclear localization of DISC1. We also report that DISC1 interacts with ATF4/CREB2 and a corepressor N-CoR, modulating CRE-mediated gene transcription.