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  • Original Article
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Nuclear DISC1 regulates CRE-mediated gene transcription and sleep homeostasis in the fruit fly

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.

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Acknowledgements

We thank Dr Pamela Talalay for critical reading of the article and Ms Y Lema for preparing the article. We thank Dr Ron Davis for providing us with MB-GeneSwitch flies. This work was supported by US Public Heath Service Grant MH-08401 and MH-069853 (AS), grants from Stanley (AS), S-R (AS) and NARSAD (AS, NS); KD064938 (TH); Grants-in-Aid for Scientific Research from MEXT and TARA (KFT) and Establishment of Consolidated Research Institute for Advanced Science and Medical Care from MEXT (NS).

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Correspondence to K Furukubo-Tokunaga or A Sawa.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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Sawamura, N., Ando, T., Maruyama, Y. et al. Nuclear DISC1 regulates CRE-mediated gene transcription and sleep homeostasis in the fruit fly. Mol Psychiatry 13, 1138–1148 (2008). https://doi.org/10.1038/mp.2008.101

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