Disrupted in Schizophrenia 1 and Nudel form a neurodevelopmentally regulated protein complex: implications for schizophrenia and other major neurological disorders

Disrupted In Schizophrenia 1 (DISCI) was identified as a potential susceptibility gene for schizophrenia due to its disruption by a balanced t(1;11) (q42;q14) translocation, which has been shown to cosegregate with major psychiatric disease in a large Scottish family. We have demonstrated that DISCI exists in a neurodevelopmentally regulated protein complex with Nudel. The complex is abundant at E17 and in early postnatal life but is greatly reduced in the, adult. Nudel has previously been shown to bind Lis1, a gene underlying lissencephaly in humans. Critically, we show that the predicted peptide product resulting from the Scottish translocation removes the interaction domain for Nudel. DISCI interacts with Nudel through a leucine zipper domain and binds to a novel DISC1-interaction domain on Nudel, which is independent from the Lis1 binding site. We show that Nudel is able to act as a bridge between DISCI and Lis1 to allow formation of a trimolecular complex. Nudel has been implicated to play a role in neuronal migration, together with the developmental variation in the abundance of the DISC1-Nudel complex, may implicate a defective DISCI-Nudel complex as a neurodevelopmental cause of schizophrenia. (C) 2003 Elsevier Inc. All rights reserved.