International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


POSTER 163 - CORRECTION OF PATHOLOGICAL AGGRESSION IN THE ‘FIERCE’ MOUSE BY

HUMAN NUCLEAR RECEPTOR 2E1

Abrahams BS, Kwok MCH, Trinh E, Budaghzadeh S, Hossain SM, Simpson EM

University of British Columbia, Vancouver, Canada

Mouse mutagenesis is a powerful means of identifying and understanding gene-behavior interactions, but determining which observations from mouse generalize to human remains challenging. Mice deleted for nuclear receptor 2E1 (Nr2e1; known previously as Mtll, Tailless, Tll, Tlx) show nervous-system specific abnormalities including pathological aggression. It is unknown, however, whether human NR2E1 is similarly involved in the modulation of development and behavior. To test the ability of human NR2E1 to modulate behavior, we generated mice carrying human NR2E1 under the control of its endogenous regulatory elements and bred them to ‘fierce’ mutants that lack mouse Nr2e1. The presence of human NR2E1 eliminated structural brain defects and ameliorated eye abnormalities observed in fierce mutants. Excitingly, the behavior of fierce mice transgenic for human NR2E1 was indistinguishable from wild-type controls. That human NR2E1 can correct fierce brain-behavior abnormalities, supports conserved underlying mechanisms for behavior modulation, and suggests that variation at NR2E1 may contribute to human behavioral disorders. More generally, we have established an experimental paradigm in which to functionally evaluate the role of human genes in behavior. Use of this approach may permit the assessment of candidate psychiatric disease genes, or specific allelic variants, for which evidence is either lacking, or exists but is equivocal.

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