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Annotation

Li W, Zhou Y, Jentsch JD, Brown RA, Tian X, Ehninger D, Hennah W, Peltonen L, Lönnqvist J, Huttunen MO, Kaprio J, Trachtenberg JT, Silva AJ, Cannon TD. Specific developmental disruption of disrupted-in-schizophrenia-1 function results in schizophrenia-related phenotypes in mice. Proc Natl Acad Sci U S A . 2007 Nov 13 ; 104(46):18280-5. PubMed Abstract

Comments on Paper and Primary News
Primary News: DISC1 Fragment Ties Schizophrenia-like Symptoms to Development in Mice

Comment by:  John Roder
Submitted 30 November 2007 Posted 30 November 2007

Some observations on the new report by Li and colleagues: this work is the first to map subregions of DISC1 and to show that a region that binds Nudel and LIS1 is important in generating schizophrenia-like perturbations in vivo. The authors express DISC1 C-terminus in mice, which interacts with Nudel and LIS1. They showed less native mouse DISC1 associations with Nudel mouse following gene induction. This suggests a dominant-negative mechanism.

No data was shown on native DISC1 levels following induction. Work from the Sawa lab shows that if murine DISC1 levels are reduced in non-engineered mice using RNAi, severe perturbations in development of nervous system are seen (Kamiya et al., 2005); however, behavior was not measured in this study. Severe perturbations would be expected based on the neonatal ventral hippocampal lesion model. In this latter model early brain lesions lead to later impairments in PPI and other behaviors consistent with schizophrenic-like behavior.

They use a promoter only expressed in the forebrain,...  Read more


View all comments by John Roder

Primary News: DISC1 Fragment Ties Schizophrenia-like Symptoms to Development in Mice

Comment by:  Akira Sawa, SRF Advisor
Submitted 3 December 2007 Posted 3 December 2007

DISC1 may be a promising entry point to explore important disease pathways for schizophrenia and related mental conditions; thus, animal models that can provide us with insights into the pathways involving DISC1 may be helpful. In this sense, the new animal model reported by Li et al. (Silva and Cannon’s group at UCLA) has great significance in this field.

They made mice expressing a short domain of DISC1 that may block interaction of DISC1 with a set of protein interactors, including NUDEL/NDEL1 and LIS1. This approach, if the domain is much shorter, will be an important methodology in exploring the disease pathways based on protein interactions. Although the manuscript is excellent, and appropriate as the first report, the domain expressed in the transgenic mice can interact with more than 30-40 proteins, and the phenotypes that the authors observed might not be attributable to the disturbance of protein interactions of DISC1 and NUDEL or LIS1.

Now we have at least five different types of animal models for DISC1, all of which have unique advantages and...  Read more


View all comments by Akira Sawa

Primary News: DISC1 Fragment Ties Schizophrenia-like Symptoms to Development in Mice

Comment by:  David J. Porteous, SRF Advisor
Submitted 21 December 2007 Posted 22 December 2007

On the DISC1 bus
You wait ages for a bus, then a string of them come one behind the other. First, Koike et al. (2006) reported that the 129 strain of mouse had a small detection of the DISC1 gene and this was associated with a deficit on a learning task. The interpretation of this observation was somewhat complicated by the subsequent recognition that the majority, if not all, major DISC1 isoforms are unaffected by the deletion, but this needs further work (Ishizuka et al., 2007). Then, Clapcote et al. (2007) provided a very detailed characterization of two independent ENU-induced mouse missense mutations of DISC1, showing selective brain shrinkage and marked behavioral abnormalities that in one mutant were schizophrenia-like, the other more akin to mood disorder. Importantly, these phenotypes could be differentially rescued by antipsychotics or antidepressants. The main finger pointed to disruption of the interaction with PDE4...  Read more


View all comments by David J. Porteous
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