Title: Functional Equivalence of Orphan Nuclear Receptor 2E1 between Mouse and Human: From Sequence to Behaviour
Name: Brett S. Abrahams
Year: 2003
Type: Dissertation Fellowship
Summary: Worldwide, ten percent of adults suffer from a mental illness or behavioural disorder at any given time (Lopez and Murray 1998). Violent behaviour is central to many forms of mental illness (Gothelf, Apter et al. 1997; APA 2000) and is itself a primary cause of mortality amongst individuals 15-45 years of age (Krug, Dahlberg et al. 2002). Although 'fierce' mice deleted for nuclear receptor 2E1 (Nr2e1) 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. 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.
Bibliography: Abrahams, B. S., G. M. Mak, et al. (2002). "Novel Vertebrate Genes and Putative Regulatory Elements Identified at Kidney Disease and NR2E1/fierce Loci." Genomics 80(1): 45-53.

Abrahams, B. S., M. C. Kwok, et al. (2005). "Pathological aggression in "fierce" mice corrected by human nuclear receptor 2E1." J Neurosci 25(27): 6263-70.