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.

[1]  P. Rashbass,et al.  Influence of PAX6 Gene Dosage on Development: Overexpression Causes Severe Eye Abnormalities , 1996, Cell.

[2]  P Chambon,et al.  Impaired locomotion and dopamine signaling in retinoid receptor mutant mice. , 1998, Science.

[3]  A. Monaghan,et al.  The mouse homolog of the orphan nuclear receptor tailless is expressed in the developing forebrain. , 1995, Development.

[4]  A. Caspi,et al.  Role of Genotype in the Cycle of Violence in Maltreated Children , 2002, Science.

[5]  R. Evans,et al.  Tlx and Pax6 co-operate genetically to establish the pallio-subpallial boundary in the embryonic mouse telencephalon , 2003, Development.

[6]  J. Joly,et al.  Morphogenesis of the optic tectum in the medaka (Oryzias latipes): A morphological and molecular study, with special emphasis on cell proliferation , 1999, The Journal of comparative neurology.

[7]  J. Moreau,et al.  Impact of environmental housing conditions on the emotional responses of mice deficient for nociceptin/orphanin FQ peptide precursor gene , 2003, Behavioural Brain Research.

[8]  C. Mahaffey,et al.  Retroposon compensatory mechanism hypothesis not supported: Zfa knockout mice are fertile. , 2003, Genomics.

[9]  I. Lucki,et al.  Automated tests for measuring the effects of antidepressants in mice , 2004, Pharmacology Biochemistry and Behavior.

[10]  C. Mahaffey,et al.  Fierce: a new mouse deletion of Nr2e1; violent behaviour and ocular abnormalities are background-dependent , 2002, Behavioural Brain Research.

[11]  Hee-Sup Shin,et al.  Mutant Mice and Neuroscience: Recommendations Concerning Genetic Background , 1997, Neuron.

[12]  E. Simpson,et al.  The dark phase improves genetic discrimination for some high throughput mouse behavioral phenotyping , 2004, Genes, brain, and behavior.

[13]  S. Goodart,et al.  Mice Expressing the Human CYP7A1 Gene in the Mouse CYP7A1 Knock-out Background Lack Induction of CYP7A1 Expression by Cholesterol Feeding and Have Increased Hypercholesterolemia When Fed a High Fat Diet* , 2002, The Journal of Biological Chemistry.

[14]  A. Goodman.  Three independent lines of evidence suggest retinoids as causal to schizophrenia. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[15]  K. Umesono,et al.  The orphan nuclear receptor Tlx regulates Pax2 and is essential for vision. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[16]  B. Hogan,et al.  Haploinsufficient Bmp4 ocular phenotypes include anterior segment dysgenesis with elevated intraocular pressure , 2001, BMC Genetics.

[17]  George Paxinos,et al.  The Mouse Brain in Stereotaxic Coordinates , 2001 .

[18]  Ravinesh A. Kumar,et al.  Unexpected embryonic stem (ES) cell mutations represent a concern in gene targeting: Lessons from “fierce” mice , 2004, Genesis.

[19]  Michael Knapp,et al.  Functional PAX-6 gene-linked polymorphic region: potential association with paranoid schizophrenia , 1999, Biological Psychiatry.

[20]  Francis J McMahon,et al.  Genomewide linkage analyses of bipolar disorder: a new sample of 250 pedigrees from the National Institute of Mental Health Genetics Initiative. , 2003, American journal of human genetics.

[21]  J. Heckenlively,et al.  Mouse fundus photography and angiography: a catalogue of normal and mutant phenotypes. , 1999, Molecular vision.

[22]  G. Sedvall,et al.  NURR1 mutations in cases of schizophrenia and manic-depressive disorder. , 2000, American journal of medical genetics.

[23]  Christopher J. Carroll,et al.  Rescue of the Friedreich's ataxia knockout mouse by human YAC transgenesis , 2001, Neurogenetics.

[24]  D. Nelson,et al.  (Over)correction of FMR1 deficiency with YAC transgenics: behavioral and physical features. , 2000, Human molecular genetics.

[25]  V. Arolt,et al.  S100B in schizophrenic psychosis. , 2004, International review of neurobiology.

[26]  P. Tucker,et al.  Math5 encodes a murine basic helix-loop-helix transcription factor expressed during early stages of retinal neurogenesis. , 1998, Development.

[27]  J. O'Brien,et al.  Glial fibrillary acidic protein in late life major depressive disorder: an immunocytochemical study , 2002, Journal of neurology, neurosurgery, and psychiatry.

[28]  Qiang Wu,et al.  The Tlx Gene Regulates the Timing of Neurogenesis in the Cortex , 2004, The Journal of Neuroscience.

[29]  M. Daly,et al.  Genomewide linkage analysis of bipolar disorder by use of a high-density single-nucleotide-polymorphism (SNP) genotyping assay: a comparison with microsatellite marker assays and finding of significant linkage to chromosome 6q22. , 2004, American journal of human genetics.

[30]  A. Monaco,et al.  Molecular evolution of FOXP2, a gene involved in speech and language , 2002, Nature.

[31]  K. Umesono,et al.  Cell-Type-Specific Regulation of the Retinoic Acid Receptor Mediated by the Orphan Nuclear Receptor TLX , 2000, Molecular and Cellular Biology.

[32]  P. Gass,et al.  Defective limbic system in mice lacking the tailless gene , 1997, Nature.

[33]  A. Taylor,et al.  Psychiatric disorder and cognitive function in a family with an inherited novel mutation of the developmental control gene PAX6. , 1999, Psychiatric genetics.

[34]  Vera Baumans,et al.  Modulation of aggression in male mice: influence of group size and cage size , 2001, Physiology & Behavior.

[35]  J. Hodgson,et al.  Human huntingtin derived from YAC transgenes compensates for loss of murine huntingtin by rescue of the embryonic lethal phenotype. , 1996, Human molecular genetics.

[36]  F. Gage,et al.  Expression and function of orphan nuclear receptor TLX in adult neural stem cells , 2004, Nature.

[37]  M C O'Donovan,et al.  The molecular genetics of schizophrenia: new findings promise new insights , 2004, Molecular Psychiatry.

[38]  C. H. Chen,et al.  Mutation analysis of the human NR4A2 gene, an essential gene for midbrain dopaminergic neurogenesis, in schizophrenic patients. , 2001, American journal of medical genetics.

[39]  A. Monaghan,et al.  Expression of the transcription factor, tailless, is required for formation of superficial cortical layers. , 2003, Cerebral cortex.

[40]  K. Campbell,et al.  Tlx Controls Proliferation and Patterning of Lateral Telencephalic Progenitor Domains , 2003, The Journal of Neuroscience.

[41]  P. McGuffin,et al.  The genetic basis for psychiatric illness in man * , 2002, The European journal of neuroscience.

[42]  L. Foroni,et al.  The human homologue of the Drosophila tailless gene (TLX): characterization and mapping to a region of common deletion in human lymphoid leukemia on chromosome 6q21. , 1998, Genomics.

[43]  宮脇 貴也.  Tlx, an orphan nuclear receptor, regulates cell numbers and astrocyte development in the developing retina , 2004 .

[44]  B. Abrahams,et al.  Metaphase FISHing of transgenic mice recommended: FISH and SKY define BAC‐mediated balanced translocation , 2003, Genesis.

[45]  J. Ward,et al.  Diminished Hepatocellular Proliferation in Mice Humanized for the Nuclear Receptor Peroxisome Proliferator-Activated Receptor α , 2004, Cancer Research.

[46]  E. Hattori,et al.  Distribution of haplotypes derived from three common variants of the NR4A2 gene in Japanese patients with schizophrenia , 2003, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[47]  V. Hartenstein,et al.  Control of early neurogenesis of the Drosophila brain by the head gap genes tll, otd, ems, and btd. , 1997, Developmental biology.