698 VOLUME 18 | NUMBER 5 | MAY 2015 NATURE NEUROSCIENCE ARTICLES Schizophrenia is a devastating psychiatric disorder affecting 1% of the population worldwide. The gene disrupted-in-schizophrenia 1 (DISC1) is a promising susceptibility factor for schizophrenia. The DISC1 locus was originally identified at the breakpoint of a bal- anced (1;11) (q42;q14) chromosome translocation that was found to cosegregate with schizophrenia, bipolar disorder and recurrent major depression in a large Scottish family 1,2 . Further analysis indicated that inheritance of the translocation was causal and increased the risk of these psychiatric disorders by 50-fold 1 . To understand the molecular function of DISC1, several groups have identified DISC1-interacting proteins, including nuclear dis- tribution gene E homolog-like 1 (NDEL1), growth factor receptor- bound protein 2 (GRB2), glycogen synthase kinase 3-β (GSK3β), lissencephaly-1 (LIS1), kinesin family member 5B (KIF5B), fas- ciculation and elongation protein-ζ 1 (FEZ1), girdin, kalirin and phosphodiesterase 4B 3,4 . We previously reported that DISC1 is required for the transport of some key regulators of axon outgrowth, including the NDEL1–LIS1–14-3-3ε complex and GRB2 through the kinesin-1 motor complex 5,6 . These results indicate that DISC1 functions as an adaptor molecule to link cargo molecules to kinesin-1 during neurodevelopment. These efforts have provided a basis for examining the processes and pathways affected by DISC1. Studies carried out in vitro and in intact cells have shown that DISC1 is involved in neurogenesis, neuronal migration, the formation of axons and dendrites and synapse formation through inter- actions with various partners 7 . We previously generated a Disc1- knockout (Disc1 −/− ) mouse and developed a set of antibodies to the N-terminal and C-terminal regions of DISC1 (DISC1n-Ab and DISC1c-Ab, respectively) 8 . Disc1 −/− mice revealed the follow- ing problems in earlier DISC1 studies: (1) the presence of DISC1 isoforms, (2) the poor specificity of commercial antibodies to DISC1 and (3) the use of improper mouse strains as pointed out previously 9 . DISC1n-Ab and DISC1c-Ab commonly detected a protein band of 100 kDa in a wild-type brain lysate but not in the Disc1 −/− lysate. Neither antibody detected any of the DISC1 isoforms postulated in previous studies 10,11 , suggesting that the isoforms are not expressed in the brain or that the expression levels are extremely low. When we examined the specificity of the commercially available antibodies to DISC1 used in previous studies 12–14 , we found that these antibodies did not detect endogenous DISC1, presumably because of its low abundance 8 . Gogos and others identified a 25-bp deletion in exon 6 of Disc1 in inbred 129 mice 15,16 . They claim that the micro- deletion in Disc1 causes a frame shift and interferes with the production of endogenous DISC1. We confirmed that the 129 and ICR outbred mouse strains 8 , which were employed in the earlier DISC1 studies 14,17–19 , carried the same deletion and that these mouse strains did not express DISC1. In the present study, it was reasonable to use the Disc1 −/− mouse to evaluate the physiological function of DISC1. 1 Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, Nagoya, Aichi, Japan. 2 JST, CREST, Tokyo, Japan. 3 Department of Physiology, Graduate School of Medicine, Nagoya University, Nagoya, Aichi, Japan. 4 Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, Kodaira, Tokyo, Japan. 5 Department of Anatomy and Cell Biology, Graduate School of Medicine, Nagoya University, Nagoya, Aichi, Japan. 6 Department of Developmental and Regenerative Biology, Graduate School of Medical Science, Nagoya City University, Nagoya, Aichi, Japan. 7 Department of Neural Regeneration and Cell Communication, Mie University Graduate School of Medicine, Tsu, Mie, Japan. 8 Department of Neuronal Cell Biology, Okazaki Institute for Integrative Bioscience and National Institute for Basic Biology, National Institutes of Natural Sciences, Okazaki, Aichi, Japan. 9 Department of Physiology, Keio University School of Medicine, Shinjuku, Tokyo, Japan. 10 Brain Science Institute, RIKEN, Wako, Saitama, Japan. Correspondence should be addressed to K. Kaibuchi (kaibuchi@med.nagoya-u.ac.jp). Received 19 December 2014; accepted 22 February 2015; published online 30 March 2015; doi:10.1038/nn.3984 Disrupted-in-schizophrenia 1 regulates transport of ITPR1 mRNA for synaptic plasticity Daisuke Tsuboi 1,2 , Keisuke Kuroda 1,2 , Motoki Tanaka 3 , Takashi Namba 1,2 , Yukihiko Iizuka 1,2 , Shinichiro Taya 1,2,4 , Tomoyasu Shinoda 1,5 , Takao Hikita 1,6 , Shinsuke Muraoka 1 , Michiro Iizuka 2,7 , Ai Nimura 1 , Akira Mizoguchi 7 , Nobuyuki Shiina 8 , Masahiro Sokabe 3 , Hideyuki Okano 9 , Katsuhiko Mikoshiba 10 & Kozo Kaibuchi 1,2 Disrupted-in-schizophrenia 1 (DISC1) is a susceptibility gene for major psychiatric disorders, including schizophrenia. DISC1 has been implicated in neurodevelopment in relation to scaffolding signal complexes. Here we used proteomic analysis to screen for DISC1 interactors and identified several RNA-binding proteins, such as hematopoietic zinc finger (HZF), that act as components of RNA-transporting granules. HZF participates in the mRNA localization of inositol-1,4,5-trisphosphate receptor type 1 (ITPR1), which plays a key role in synaptic plasticity. DISC1 colocalizes with HZF and ITPR1 mRNA in hippocampal dendrites and directly associates with neuronal mRNAs, including ITPR1 mRNA. The binding potential of DISC1 for ITPR1 mRNA is facilitated by HZF. Studies of Disc1-knockout mice have revealed that DISC1 regulates the dendritic transport of Itpr1 mRNA by directly interacting with its mRNA. The DISC1-mediated mRNA regulation is involved in synaptic plasticity. We show that DISC1 binds ITPR1 mRNA with HZF, thereby regulating its dendritic transport for synaptic plasticity. npg © 2015 Nature America, Inc. All rights reserved.