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

Naoya Sawamura, T. Ando, Y. Maruyama, M. Fujimuro, H. Mochizuki, K. Honjo, M. Shimoda, H. Toda, T. Sawamura-Yamamoto, L. A. Makuch, A. Hayashi, K. Ishizuka, N. G. Cascella, A. Kamiya, N. Ishida, T. Tomoda, T. Hai, K. Furukubo-Tokunaga, A. Sawa

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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.

Original languageEnglish
Pages (from-to)1138-1148
Number of pages11
JournalMolecular Psychiatry
Volume13
Issue number12
DOIs
Publication statusPublished - 2008 Dec

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Keywords

  • ATF4
  • CREB
  • Depression
  • Mood disorder
  • Schizophrenia
  • Sleep

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

Cite this

Sawamura, N., Ando, T., Maruyama, Y., Fujimuro, M., Mochizuki, H., Honjo, K., Shimoda, M., Toda, H., Sawamura-Yamamoto, T., Makuch, L. A., Hayashi, A., Ishizuka, K., Cascella, N. G., Kamiya, A., Ishida, N., Tomoda, T., Hai, T., Furukubo-Tokunaga, K., & Sawa, A. (2008). Nuclear DISC1 regulates CRE-mediated gene transcription and sleep homeostasis in the fruit fly. Molecular Psychiatry, 13(12), 1138-1148. https://doi.org/10.1038/mp.2008.101