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Functional equivalence of orphan nuclear receptor 2E1 between mouse and human: from sequence to behaviour Abrahams, Brett S.

Abstract

Worldwide, ten percent of adults suffer from a mental illness or behavioural disorder at any given time (Lopez & Murray 1998). Violent behaviour is central to many forms of mental illness (Gothelf et al 1997, APA 2000) and is itself a primary cause of mortality amongst individuals 15-45 years of age (Krug et al 2002). Although 'fierce' mice deleted for nuclear receptor 2E1 (Nr2el) show pathological aggression, it is unknown whether human NR2E1 is similarly involved in the modulation of development and behaviour. To better understand the role of human NR2E1 in brain development and behaviour, I undertook a series of studies employing computational analyses and transgenic mouse technology. A comparative sequence analysis of the NR2E1 locus in human, mouse, and the puffer fish Fugu Rubripes highlighted an unusually high degree of structural conservation across evolution, identified putative regulatory elements, and facilitated the generation of novel transgenic mouse strains. Characterization of a panel of random insertion transgenic mice carrying an Nr2e 1 -spanning clone indicated that standard molecular techniques failed to identify problematic insertions that would have interfered with downstream applications if not identified by molecular cytogenetic analyses. These results have implications for characterization of new transgenic mouse strains and helped shaped my subsequent studies. Finally, to test the ability of human NR2E1 to modulate mouse behaviour, I generated mice carrying human NR2E1 under its endogenous regulatory elements and bred them to fierce mutant mice. I determined that human NR2E1 is sufficient to correct fierce brain-behaviour abnormalities, supporting conserved mechanisms for modulation of behaviour between the two species. These data represent the first example of a human gene correcting mouse behaviour. They also provide a paradigm to enable functional evaluation of candidate psychiatric disease genes, and suggest that variation at NR2E1 may contribute to human behavioural disorders.

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