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Human Molecular Genetics Advance Access published online on October 11, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl407
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© 2006 The Author(s) This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received July 21, 2006
Revised October 3, 2006
Accepted October 3, 2006

Article

DISC1-NDEL1/NUDEL protein interaction, an essential component for neurite outgrowth, is modulated by genetic variations of DISC1

Atsushi Kamiya 1, Toshifumi Tomoda 2, Jennifer Chang 1, Manabu Takaki 1, Caixin Zhan 2, Masahiko Morita 1, Matthew B. Cascio 3, Sarah Elashvili 1, Hiroyuki Koizumi 4, Yasukazu Takanezawa 4, Faith Dickerson 5, Robert Yolken 6, Hiroyuki Arai 4, and Akira Sawa 7 *

1 Department of Psychiatry and Behavioral Sciences
2 Division of Neurosciences, Beckman Research Institute of City of Hope, Los Angeles, CA, USA
3 Department of Neuroscience
4 Department of Health Chemistry, Faculty of Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
5 Stanley Research Center, Sheppard Pratt Health System, Baltimore, MD, USA
6 Stanley Laboratory of Developmental Neurovirology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
7 Department of Psychiatry and Behavioral Sciences; Department of Neuroscience; Program in Cellular and Molecular Medicine

* To whom correspondence should be addressed.
Akira Sawa, E-mail: asawa1{at}jhmi.edu


  Abstract

Disrupted-In-Schizophrenia-1 (DISC1) is a unique susceptibility gene for major mental conditions, due to the segregation of its genetic variant with hereditary psychosis in a Scottish pedigree. Genetic association studies reproducibly suggest involvement of DISC1 in both schizophrenia and bipolar disorder in several ethnic groups. The DISC1 protein is multifunctional, and a pool of DISC1 in the dynein motor complex is required for neurite outgrowth in PC12 cells as well as proper neuronal migration and dendritic arborization in the developing cerebral cortex in vivo. Here, we show that a specific interaction between DISC1 and nuclear distribution element-like (NDEL1/NUDEL) is required for neurite outgrowth in differentiating PC12 cells. Among several components of the dynein motor complex, DISC1 and NDEL1 are selectively upregulated during neurite outgrowth upon differentiation in PC12 cells. The NDEL1 binding site of DISC1 was narrowed down to a small portion of exon 13, corresponding to amino acids 802-835 of DISC1. We demonstrate that genetic variants of DISC1 proximal to the NDEL1 binding site affect the interaction between DISC1 and NDEL1.


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