Pathological aggression in "fierce" mice corrected by human nuclear receptor 2E1.
"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.
Abrahams
Brett S
BS
Graduate Program in Neuroscience, British Columbia Research Institute for Children's and Women's Health, University of British Columbia, Vancouver, British Columbia, V5Z 4H4, Canada.
Kwok
Melvin C H
MC
Trinh
Eric
E
Budaghzadeh
Saeed
S
Hossain
Sazzad M
SM
Simpson
Elizabeth M
EM
D000374:Aggression / Q000502:physiology*; D000378:Agonistic Behavior / Q000502:physiology; D000818:Animals; D001921:Brain / Q000002:abnormalities* / Q000196:embryology; D002540:Cerebral Cortex / Q000002:abnormalities; D000013:Congenital Abnormalities / Q000196:embryology / Q000235:genetics / Q000628:therapy; D003433:Crosses, Genetic; D005106:Exploratory Behavior / Q000502:physiology; D005124:Eye Abnormalities / Q000196:embryology / Q000235:genetics* / Q000628:therapy; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009830:Olfactory Bulb / Q000002:abnormalities; D057093:Orphan Nuclear Receptors; D010641:Phenotype; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D012045:Regulatory Sequences, Nucleic Acid; D012160:Retina / Q000002:abnormalities; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013045:Species Specificity; D013731:Territoriality
C088601:NR2E1 protein, human; C490258:Nr2e1 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear