Fierce: a new mouse deletion of Nr2e1; violent behaviour and ocular abnormalities are background-dependent

Abstract

A new spontaneous mouse mutation named fierce (frc) is deleted for the nuclear receptor Nr2e1 gene (also known as Tlx, mouse homolog of Drosophila tailless). The fierce mutation is genetically and phenotypically similar to Nr2e1 targeted mutations previously studied on segregating genetic backgrounds. However, we have characterized the fierce brain, eye, and behavioural phenotypes on three defined genetic backgrounds (C57BL/6J, 129P3/JEms, and B6129F1). The data revealed many novel and background-dependent phenotypic characteristics. Whereas abnormalities in brain development, hypoplasia of cerebrum and olfactory lobes, were consistent on all three backgrounds, our novel finding of enlarged ventricles in 100% and overt hydrocephalus in up to 30% of fierce mice were unique to the C57BL/6J background. Developmental eye abnormalities were also background-dependent with B6129F1-frc mice having less severe thinning of optic layers and less affected electroretinogram responses. Impaired regression of hyaloid vessels was observed in all backgrounds. Furthermore, retinal vessels were deficient in size and number in 129P3/JEms-frc and B6129F1-frc mice but almost entirely absent in C57BL/6J-frc mice. We present the first standardized behavioural tests conducted on Nr2e1 mutant mice and show that C57BL/6J-frc and B6129F1-frc mice have deficits in sensorimotor assays and are hyperaggressive in both sexes and backgrounds. However, C57BL/6J-frc mice were significantly more aggressive than B6129F1-frc mice. Overall, this extensive characterization of the fierce mutation is essential to its application for the study of behavioural, and brain and eye developmental disorders. In addition, the background-dependent differences revealed will enable the identification of important genetic modifiers.

Tailless and Atrophin control Drosophila aggression by regulating neuropeptide signalling in the pars intercerebralis

“…We first asked whether transcriptional control of aggression is conserved between fruit flies and mice and focused on the role of the orphan nuclear receptor orthologue of Nr2e1 in this complex behaviour. In mice, a deletion of the Nr2e1 locus results in brain developmental defects and extreme aggression, although it is not known whether the developmental and behavioural effects are directly linked 19,[27][28][29] . The Drosophila genome harbours two Nr2e1 orthologues 20,21 , tailless (tll) and dissatisfaction (dsf) (Supplementary Fig.…”

“…Loss of Nr2e1 in mice causes abnormal brain development in addition to extreme aggression 19,[27][28][29] . However, it is unclear whether these brain defects cause the aggression phenotype in mice or whether the behavioural abnormalities are independent from the developmental defects.…”

“…Thus, we have shown that three key mechanisms involved in the control of mammalian aggression are also involved in the control of fly aggression and that they may in fact be a single mechanism. The orphan nuclear receptor Nr2e1 or Tailless is known to have conserved co-repressors 25 , binding sites 24 and targets 26 , and loss of ARTICLE function of this gene in mice has a strong aggression phenotype 19,[27][28][29] that can be rescued with a human genomic transgene 29 . The fly harbours two Nr2e1 orthologues 20,21 , tailless (tll) and dissatisfaction (dsf), the former best known for its essential role in early embryogenesis 22,23 the latter known for its effect on courtship 37 .…”

“…In addition, some of the known targets are conserved between mice and flies 26 . A deletion of the mouse gene causes abnormal brain development and extreme aggression 19,[27][28][29] . These phenotypes are rescued with a human transgene covering the human genomic locus demonstrating molecular conservation between mice and humans even at the level of the regulatory regions of this locus 29 .…”

The Orphan Nuclear Receptor TLX/NR2E1 in Neural Stem Cells and Diseases

“…TLX is the human homologue of the Drosophila tailless (tll) gene and is predominantly expressed in the developing brain and retina [5][6][7]. Human TLX and its homologues in Drosophila, zebrafish, and mouse have conserved functions in brain and retinal development [8][9][10]. TLX as well as its homologues in other species predominantly acts as a transcriptional repressor, although a function in transcriptional activation has also been suggested in some studies [11,12].…”