1. ¹Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
2. ²The 21st Century Center of Excellence Program, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
3. ³Department of Anatomy and Developmental Neurobiology, School of Medicine, Kobe University, Kobe, Japan
4. ⁴The Osaka-Hamamatsu Joint Research Center for Child Mental Development, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
5. ⁵Pharmacology Research Laboratory, Tanabe Seiyaku Co. Ltd, Yodogawa-ku, Osaka, Japan
6. ⁶Department of Brain Science, Graduate School of Medicine and Dentistry, Okayama University, Okayama, Japan
7. ⁷Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan
8. ⁸Department of Neurobiology, Graduate School of Medicine, Chiba University, Chiba, Japan
9. ⁹Department of Anatomy and Neuroscience, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan

Correspondence: Dr S Matsuzaki, Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail: s-matsuzaki@anat2.med.osaka-u.ac.jp

¹⁰These authors contributed equally to this work.

Received 11 October 2005; Revised 11 September 2006; Accepted 11 December 2006; Published online 23 January 2007.

Abstract

Disrupted-in-schizophrenia 1 (DISC1) is a gene disrupted by a (1;11) (q42.1;q14.3) translocation that segregates with major psychiatric disorders in a Scottish family. To investigate how DISC1 confers susceptibility to psychiatric disorders, we previously identified fasciculation and elongation protein zeta-1 and Kendrin as DISC1-interacting molecules in a yeast two-hybrid screen of a human brain complementary DNA library. Here, we have further identified a novel DISC1-interacting protein, termed DISC1-Binding Zinc-finger protein (DBZ), which has a predicted C₂H₂-type zinc-finger motif and coiled-coil domains. DBZ was co-immunoprecipitated with DISC1 in lysates of PC12 cells and rat brain tissue. The domain of DISC1 interacting with DBZ was close to the translocation breakpoint in the DISC1 gene. DBZ messenger RNA (mRNA) was expressed in human brains, but not in peripheral tissues. In situ hybridization revealed high expression of DBZ mRNA in the hippocampus, olfactory tubercle, cerebral cortex and striatum in rats. Because this pattern of localization was similar to that of the pituitary adenylate cyclase (PAC₁) receptor for pituitary adenylate cyclase-activating polypeptide (PACAP), which has recently been implicated in neuropsychological functions, we examined whether DISC1/DBZ interaction was involved in the PACAP signaling pathway. PACAP upregulated DISC1 expression and markedly reduced the association between DISC1 and DBZ in PC12 cells. A DISC1-binding domain of DBZ reduced the neurite length in PC12 cells after PACAP stimulation and in primary cultured hippocampal neurons. The present results provide some new molecular insights into the mechanisms of neuronal development and neuropsychiatric disorders.