Pathological aggression in "fierce" mice corrected by human nuclear receptor 2E1

被引:41
作者
Abrahams, BS
Kwok, MCH
Trinh, E
Budaghzadeh, S
Hossain, SM
Simpson, EM [1 ]
机构
[1] Univ British Columbia, Grad Program Neurosci, Vancouver, BC V5Z 4H4, Canada
[2] Univ British Columbia, British Columbia Res Inst Childrens & Womens Hlth, Ctr Mol Med & Therapeut, Vancouver, BC V5Z 4H4, Canada
[3] Univ British Columbia, Dept Med Genet, Vancouver, BC V5Z 4H4, Canada
关键词
6q21-6q22; behavior; genetic disease; Tlx; transgenic rescue; violence;
D O I
10.1523/JNEUROSCI.4757-04.2005
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
''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.
引用
收藏
页码:6263 / 6270
页数:8
相关论文
共 49 条
[31]  
Nguyen V, 1999, J COMP NEUROL, V413, P385, DOI 10.1002/(SICI)1096-9861(19991025)413:3<385::AID-CNE3>3.0.CO
[32]  
2-P
[33]   Impact of environmental housing conditions on the emotional responses of mice deficient for nociceptin/orphanin FQ peptide precursor gene [J].
Ouagazzal, AM ;
Moreau, JL ;
Pauly-Evers, M ;
Jenck, ZF .
BEHAVIOURAL BRAIN RESEARCH, 2003, 144 (1-2) :111-117
[34]   The molecular genetics of schizophrenia: findings promise new insights [J].
Owen, MJ ;
Williams, NM ;
O'Donovan, MC .
MOLECULAR PSYCHIATRY, 2004, 9 (01) :14-27
[35]   (Over)correction of FMR1 deficiency with YAC transgenics: behavioral and physical features [J].
Peier, AM ;
McIlwain, KL ;
Kenneson, A ;
Warren, ST ;
Paylor, R ;
Nelson, DL .
HUMAN MOLECULAR GENETICS, 2000, 9 (08) :1145-1159
[36]  
Pook MA, 2001, NEUROGENETICS, V3, P185
[37]  
Rothermundt M, 2004, INT REV NEUROBIOL, V59, P445
[38]   The Tlx gene regulates the timing of neurogenesis in the cortex [J].
Roy, K ;
Kuznicki, K ;
Wu, Q ;
Sun, ZX ;
Bock, D ;
Schutz, G ;
Vranich, N ;
Monaghan, AP .
JOURNAL OF NEUROSCIENCE, 2004, 24 (38) :8333-8345
[39]   Influence of PAX6 gene dosage on development: Overexpression causes severe eye abnormalities [J].
Schedl, A ;
Ross, A ;
Lee, M ;
Engelkamp, D ;
Rashbass, P ;
vanHeyningen, V ;
Hastie, ND .
CELL, 1996, 86 (01) :71-82
[40]   Expression and function of orphan nuclear receptor TLX in adult neural stem cells [J].
Shi, YH ;
Lie, DC ;
Taupin, P ;
Nakashima, K ;
Ray, J ;
Yu, RT ;
Gage, FH ;
Evans, RM .
NATURE, 2004, 427 (6969) :78-83