5 Mar 2006
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.
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