Disrupted-in-Schizophrenia-1 (DISC-1): mutant truncation prevents binding to NudE-like (NUDEL) and inhibits neurite outgrowth.
Disrupted-in-Schizophrenia-1 (DISC-1) is a gene whose mutant truncation is associated with major psychiatric illness with a predominance of schizophrenic symptomatology. We have cloned and characterized rodent DISC-1. DISC-1 expression displays pronounced developmental regulation with the highest levels in late embryonic life when the cerebral cortex develops. In yeast two-hybrid analyses, DISC-1 interacts with a variety of cytoskeletal proteins. One of these, NudE-like (NUDEL), is associated with cortical development and is linked to LIS-1, the disease gene for a form of lissencephaly, a disorder of cortical development. The disease mutant form of DISC-1 fails to bind NUDEL. Expression of mutant, but not wild-type, DISC-1 in PC12 cells reduces neurite extension. As schizophrenia is thought to reflect defects in cortical development that are determined by cytoskeletal protein activities, the cellular disturbances we observe with mutant DISC-1 may be relevant to psychopathologic mechanisms.
Ozeki
Yuji
Y
Division of Neurobiology and Department of Psychiatry, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21205, USA.
Tomoda
Toshifumi
T
Kleiderlein
John
J
Kamiya
Atsushi
A
Bord
Lyuda
L
Fujii
Kumiko
K
Okawa
Masako
M
Yamada
Naoto
N
Hatten
Mary E
ME
Snyder
Solomon H
SH
Ross
Christopher A
CA
Sawa
Akira
A
D000818:Animals; D003001:Cloning, Molecular; D003546:Cysteine Endopeptidases; D017931:DNA Primers; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D016501:Neurites / Q000502:physiology*; D011485:Protein Binding; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D012697:Serine Endopeptidases / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism
C412476:DISC1 protein, human; D017931:DNA Primers; C498795:Disc1 protein, rat; D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; D012697:Serine Endopeptidases; D003546:Cysteine Endopeptidases; C516549:Ndel1 protein, rat