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Pathological aggression in "fierce" mice corrected by human nuclear receptor 2E1
Brett S Abrahams1, Melvin C H Kwok, Eric Trinh
1Graduate Program in Neuroscience, British Columbia Research Institute for Children's and Women's Health, University of British Columbia, Vancouver, British Columbia, V5Z 4H4, Canada.
Summary
Human nuclear receptor 2E1 (NR2E1) can rescue aggressive behavior and developmental defects in mice lacking the gene. This suggests NR2E1 may play a role in human behavioral disorders.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- The nuclear receptor 2E1 (NR2E1) gene is crucial for normal brain and eye development.
- Mutations in NR2E1 lead to severe developmental abnormalities and pathological aggression in mice ('fierce' mice).
Purpose of the Study:
- To assess the functional equivalency between mouse and human NR2E1.
- To investigate the potential role of human NR2E1 in regulating behavior and development.
- To explore the relevance of NR2E1 to human behavioral disorders.
Main Methods:
- Generated transgenic mice carrying a human NR2E1 genomic clone.
- Bred these transgenic mice with 'fierce' mice lacking the endogenous mouse NR2E1 gene.
- Evaluated structural brain defects, eye abnormalities, and behavioral phenotypes in the resulting 'rescue' mice.
Main Results:
- Transgenic expression of human NR2E1 in 'fierce' mice corrected structural brain defects.
- Eye abnormalities were significantly ameliorated in the 'rescue' mice.
- Behavioral analysis revealed that 'rescue' mice were indistinguishable from control mice, indicating successful rescue of aggression.
Conclusions:
- The human NR2E1 gene, under the control of its own regulatory elements, can functionally replace the mouse NR2E1 gene.
- The mechanisms underlying behavioral abnormalities in 'fierce' mice appear conserved between mice and humans.
- These findings support the hypothesis that variations in NR2E1 may contribute to human behavioral disorders, and the rescue paradigm is valuable for studying other genes implicated in psychiatric diseases.