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The Journal of Neuroscience, July 6, 2005, 25(27):6263-6270; doi:10.1523/JNEUROSCI.4757-04.2005

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Neurobiology of Disease
Pathological Aggression in "Fierce" Mice Corrected by Human Nuclear Receptor 2E1

Brett S. Abrahams,^1,2,3 Melvin C. H. Kwok,^2,3 Eric Trinh,^2,3 Saeed Budaghzadeh,^2,3 Sazzad M. Hossain,^2,3 and Elizabeth M. Simpson^1,2,3

¹Graduate Program in Neuroscience and ²Centre for Molecular Medicine and Therapeutics, British Columbia Research Institute for Children's and Women's Health, and ³Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4

"Fierce" mice, homozygous for the deletion of nuclear receptor 2E1 (NR2E1), show abnormal brain-eye development and pathological aggression. To evaluate functional equivalency between mouse and human NR2E1, we generated mice transgenic for a genomic clone spanning the human NR2E1 locus and bred these animals to fierce mice deleted for the corresponding mouse gene. In fierce mutants carrying human NR2E1, structural brain defects were eliminated and eye abnormalities ameliorated. Excitingly, behavior in these "rescue" mice was indistinguishable from controls. Because no artificial promoter was used to drive transgene expression, promoter and regulatory elements within the human NR2E1 clone are functional in mouse. Normal behavior in rescue animals suggests that mechanisms underlying the behavioral abnormalities in fierce mice may also be conserved in humans. Our data support the hypothesis that variation at NR2E1 may contribute to human behavioral disorders. Use of this rescue paradigm with other genes will permit the direct evaluation of human genes hypothesized to play a causal role in psychiatric disease but for which evidence is lacking or equivocal.

Key words: 6q21-6q22; behavior; genetic disease; Tlx; transgenic rescue; violence

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Received Nov 4, 2004; revised May 20, 2005; accepted May 22, 2005.

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