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Nature Makes a DISC1-Deficient, Forgetful Mouse

6 March 2006. Any researcher who has made knockout or knock-in mice will tell you how many months and years of hard work it can be. So imagine their surprise—nay, delight—when researchers trying to knock out the murine disrupted in schizophrenia 1 (DISC1) gene discovered that nature had beaten them to the punch. Writing in the February 16 PNAS, Joseph Gogos and colleagues at Columbia University, New York, together with Maria Karayiorgou’s lab at the nearby Rockefeller University, report that the 129S6/SvEvTac strain of mice has a spontaneous mutation that truncates DISC1 in the seventh of 13 exons, cutting the protein almost in half and generating an unstable, rapidly degraded fragment. This common mouse strain, around since the 1960s and almost the only strain used for targeted mutagenesis and knockouts, might turn out to be a natural model for aspects of schizophrenia and other psychiatric disorders.

Since a translocation mutation in DISC1 was found to associate with schizophrenia in an extended Scottish family (see Millar et al., 2000), researchers have been trying to figure out what role the protein plays and how it fits in with psychiatric disorders. Ironically, joint first authors Hiroko Koike and Alexander Arguello and their colleagues discovered the truncation when trying to recapitulate that human translocation in mice. They found that the 129S6 strain is missing 25 base pairs of DNA in the sixth exon, causing a frame shift that introduces a premature stop codon some 40 bases downstream in exon 7. The mouse mutant DISC1 is, therefore, just a tad smaller than the protein coded by the DISC1 mutant in the Scottish families, which has a breakpoint just after exon 8.

Koike and colleagues found that although mRNA for DISC1 is produced at normal levels in the 129S6 strain, an antibody to the N-terminal of the protein failed to detect any truncated DISC1 in either adults or 10-day-old pups. Because the antibody readily detects full-length protein in the C57BL strain of mice, the authors concluded that truncated DISC1 must be relatively unstable.

To determine if the mutation has any effect on mouse behavior, the authors transferred a modified mouse DISC1 allele from the 129S6 strain into the C57BL/6J strain. Wild-type C57BL/6J then served as a control in behavioral tests of spatial working memory. In a delayed non-match-to-place task that is designed to challenge the prefrontal cortex (see Aultman and Moghaddam, 2001), the authors found that mice carrying the mutant DISC1 performed poorly compared with wild-type C57 mice. Despite having normal-looking brain morphology, those animals harboring the mutant gene (either homozygotes or heterozygotes) made significantly fewer correct responses when choosing which arm of a T maze they should enter in the task.

The results suggest that the mutation in mouse DISC1 has similar effects to those observed in humans. Polymorphisms in the DISC1 gene have been linked to impaired short- and long-term memory (see Cannon et al., 2005), and visual and verbal memory problems in Finnish (see Hennah et al., 2005) and North American families of Caucasian descent (see Burdick et al., 2005). However, exactly what this protein does and how it might contribute to pathology is unclear. Though the 129S6 strain does not appear to have any gross developmental problems, DISC1 has been linked to neurodevelopment. It binds to dynein motors, for example, which are needed for proper microtubule dynamics, perhaps explaining why mutant DISC1 has a subtle, though perhaps pathological impact on the development of the cerebral cortex in mice (see SRF related news story). Reduced hippocampal volume has also been associated with DISC1 polymorphisms in schizophrenia patients (see Callicott et al., 2005).

Whether or not DISC1 truly has a role in the etiology of schizophrenia, the identification of this spontaneous mutation in mice should help decipher what precisely the protein does. The strain might also be a boon for those studying other susceptibility genes. “We don't expect a single gene manipulation to give us all the anatomical, neurochemical, and behavioral effects of schizophrenia, but genes in combination just might,” said Arguello. Testing other mutations or polymorphisms in the 129S6 background might reveal genetic interactions that would otherwise be missed.—Tom Fagan.

Reference:
Koike H, Arguello PA, Kvajo M, Karayiorgou M, Gogos JA. Disc1 is mutated in the 129S6/SvEv strain and modulates working memory in mice. PNAS Early Edition. February 16, 2006. Abstract

 
Comments on News and Primary Papers
Comment by:  Anil Malhotra, SRF AdvisorKatherine E. Burdick
Submitted 7 March 2006 Posted 7 March 2006
  I recommend the Primary Papers

The two latest additions to the burgeoning DISC1 literature provide additional support for a role of this gene in cognitive function and schizophrenia, and suggest that more comprehensive studies will be useful as we move to a greater understanding of its role in CNS function. Koike et al. (2006) found that a relatively common mouse strain has a naturally occurring mutation in DISC1 resulting in a truncated form of the protein, similar in size (exon 7 vs. exon 8 disruptions) to that observed in the members of the Scottish pedigree in which the translocation was first detected. C57/BL/6J mice, into which mutant alleles were transferred, displayed significant impairments on a spatial working memory task similar to one used in humans (Lencz et al., 2003). These data are similar to those observed by our group (Burdick et al., 2005) and others (  Read more


View all comments by Anil Malhotra
View all comments by Katherine E. Burdick

Comment by:  J David Jentsch
Submitted 7 March 2006 Posted 7 March 2006
  I recommend the Primary Papers

In their recent paper, Koike et al. provide new evidence in support of a genetic determinant of working memory function in the vicinity of the mouse DISC1 gene. They report their discovery of a naturally occurring DISC1 deletion variant in the 129S6/SvEv mouse strain that leads to reduced protein expression and that provides a potentially very important new tool for analyzing the cellular and behavioral phenotypes associated with DISC1 insufficiency. Given the strong evidence of a relationship between a cytogenetic abnormality that leads to DISC1 truncation in humans and major mental illness (Millar et al., 2000), this murine model stands to greatly serve our understanding of the molecular and cellular determinants of poor cognition in schizophrenia and bipolar disorder.

The authors are parsimonious in reminding us of the substantial limitations of models such as this. Specifically, the current approach does not allow...  Read more


View all comments by J David Jentsch

Comment by:  Kirsty Millar
Submitted 13 March 2006 Posted 13 March 2006
  I recommend the Primary Papers

Disrupted In Schizophrenia 1 was first identified as a genetic susceptibility factor in schizophrenia because it is disrupted by a translocation between chromosomes 1 and 11 in a large Scottish family with a high loading of schizophrenia and related mental illness. Since then, numerous genetic studies have implicated DISC1 as a risk factor in psychiatric illness in several populations. Given the limitations on studies using brain tissue from patients, an obvious next step was to engineer knockout mice, but these have been slow in coming. As a first step toward this, Kioke and colleagues now report an unexpected naturally occurring genetic variant in the 129/SvEv mouse strain.

Kioke et al. report that the 129/SvEv mouse strain carries a 25 bp deletion in DISC1 exon 6, and that this results in a shift of open reading frame and introduction of a premature stop codon. Several embryonal stem cell lines have been isolated for the 129 strain, favoring it for gene targeting studies. However, this strain has a number of well-established behavioral characteristics (  Read more


View all comments by Kirsty Millar
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