Disease relevance of Rora

• In conclusion, we speculate that ROR agonists would increase fatty acid catabolism in muscle and suggest selective activators of ROR may have therapeutic utility in the treatment of obesity and atherosclerosis [1].
• Because hypoxia is a major feature of liver physiology and pathology, we examined the effect of this stress on Rora gene expression and RORalpha transcriptional activity [2].
• Furthermore, the apparent persistence of the embryonic ganglioside GD3 in sg/sg mice results from an early-onset reactive gliosis, together with a partial retardation in granule cell maturation [3].
• Many similarities of both the inheritance pattern and the neuropathology can be observed between olivopontocerebellar atrophies, or so-called multiple system atrophies (MSAs), and murine cerebellar mutations like Purkinje cell degeneration, nervous, staggerer, weaver, and reeler [4].
• Enhanced susceptibility of staggerer (RORalphasg/sg) mice to lipopolysaccharide-induced lung inflammation [5].

Psychiatry related information on Rora

• Rora is required for normal Bmal1 expression and consolidation of daily locomotor activity and is regulated by the core clock in the SCN [6].
• The Rora(-/-) cerebellum is qualitatively a phenocopy of the Rora(sg/sg) one, but the two strains differ slightly in their motor skills [7].
• Restoration of staggerer mouse maternal behavior following long-term breeding selection [8].
• Effects of the rearing temperature on the temporal feeding pattern of the staggerer mutant mouse [9].
• It was found that, contrary to normal mice, the staggerer mutants did not alternate spontaneously and had deficits in the acquisition of maze learning [10].

High impact information on Rora

• The recent identification of ROR2, encoding an orphan receptor tyrosine kinase, as the gene mutated in brachydactyly type B (BDB1; ref. 7) and the mesomelic dwarfing in mice homozygous for a lacZ and/or a neo insertion into Ror2 (refs 8,9) made this gene a candidate for RRS [11].
• In addition, sg heterozygotes show accelerated dendritic atrophy and cell loss, suggesting that sg has a role in mature Purkinje cells [12].
• Homozygous staggerer (sg) mice show a characteristic severe cerebellar ataxia due to a cell-autonomous defect in the development of Purkinje cells [12].
• We have genetically mapped staggerer to an interval of 160 kilobases on mouse chromosome 9 which was found to contain the gene encoding RORalpha, a member of the nuclear hormone-receptor superfamily [12].
• These results demonstrate that the amino-terminal domain and the zinc finger region work in concert to confer high affinity and specific DNA-binding properties to the ROR isoforms and suggest a novel strategy to control DNA-binding activity of nuclear receptors [13].

Chemical compound and disease context of Rora

• HepG2 human hepatoma cells were cultured for 24 h under normoxia (20% O2) or hypoxia (10, 2, and 0.1% O2) and the abundance of the Rora transcripts measured by Northern blot and semi-quantitative RT-PCR [2].
• Melatonin and RZR/ROR receptor ligand CGP 52608 induce apoptosis in the murine colonic cancer [14].
• Retinoic acid receptor-related orphan receptor (ROR) alpha4 is the predominant isoform of the nuclear receptor RORalpha in the liver and is up-regulated by hypoxia in HepG2 human hepatoma cells [2].

Biological context of Rora

• A functional genomics strategy reveals Rora as a component of the mammalian circadian clock [6].
• Using interspecific backcross analysis, we have mapped the Rora gene to mouse chromosome 9 [15].
• Embryonic to adult conversion of neural cell adhesion molecules in normal and staggerer mice [16].
• These findings suggest that there is a distinct mediolateral heterogeneity in the staggerer cerebellum with respect to transcription levels of these Purkinje cell-specific molecules, which might correlate with some cytological phenotypes [17].
• Our data suggest that the sg/sg mutation does not interfere with the transcriptional activation of these two genes, and might therefore act after the induction of specific gene expression in developing Purkinje cells [18].

Anatomical context of Rora

• There was also some delay in E leads to A conversion within the cerebral cortex of sg/sg, although phenotypically no evidence of cortical disorder has been detected [16].
• In both reeler and weaver mutant mice in the adult stage, all Purkinje cells were positive for c-fms as in the wild-type controls; however, the parasagittal bands of c-fms-positive Purkinje cells were observed even in the adult staggerer mutant [19].
• The Purkinje cells in the staggerer mutant mouse have various cellular abnormalities, including reduced cell number, ectopia, smaller size and absence of dendritic spines [17].
• The recessive mouse mutation staggerer (sg) disturbs the normal development of cerebellar Purkinje cells and affects certain functions of the immune system [20].
• Substantially lower [3H]flunitrazepam labeling was detected over the cerebellar cortex of 25-27-day-old sg/sg mutants in which the number of granule, Purkinje and Golgi cells is greatly reduced; the labeling over the deep nuclei, however, was significantly increased [21].

Associations of Rora with chemical compounds

• In this paper we have investigated expression in the staggerer Purkinje cells of the calbindin and inositol 1,4, 5-trisphosphate receptor type 1 mRNAs by in situ hybridization [17].
• The staggerer (Rora(sg/sg)) mutation is a deletion in the RORalpha gene, one member of a family of nuclear receptor genes related to the retinoic acid receptor [7].
• Furthermore, the staggerer mice display lowered plasma apoA-I/-II, decreased plasma high density lipoprotein cholesterol and triglycerides, and develop hypo-alpha-lipoproteinemia and atherosclerosis [1].
• ROR alpha gene expression in the perinatal rat cerebellum: ontogeny and thyroid hormone regulation [22].
• During cerebellar development, an approximately 3-fold increase in the cerebellar content of ROR alpha messenger RNA (mRNA) was seen in both propylthiouracil-treated, and propylthiouracil-treated and T4-replaced animals [22].

Regulatory relationships of Rora

• Interestingly, the ROR alpha-mediated transcription is further activated synergistically by RAR [23].
• Transient expression study demonstrated that transcription of the Purkinje cell protein-2 (Pcp-2) gene is activated by ROR alpha, which binds as a monomer to a single half-site motif (RORE) within the promoter region [23].
• However, the Purkinje cells of staggerer mutant mouse proved to be incapable of enhanced P400 protein expression [24].
• Our results show that IL-6 mRNA is hyperexpressed in stimulated macrophages of staggerer mutant mice [25].
• The staggerer murine mutation induces olfactory deficits [26].

Other interactions of Rora

• This result suggests an additional linkage between Ncam and the locus for the cerebellar mutation staggerer (sg) [27].
• In staggerer mice, neurons immunopositive for Parv as well as for Calb were present in outer DCN areas, likely representing ectopic PCs rather than DCN neurons [28].
• In the cerebella of two neurological granule cell-deficient mutants, weaver (wv) and staggerer (sg), parallin is not detected [29].
• Using cell-based functional assays, as well as behavioral and molecular analyses, we identified Rora as an activator of Bmal1 transcription within the SCN [6].
• CONCLUSION: That the Pcp-2 gene is a target of ROR alpha, and is suggested that its transcription is also regulated by RAR [23].

Analytical, diagnostic and therapeutic context of Rora

• To test this hypothesis, we studied the changes in ROR alpha gene expression in perinatal hypothyroid rat cerebellum and the effect of TH replacement using Northern blot analysis, ribonuclease protection assay and in situ hybridization histochemistry [22].
• An IL-1 bioassay using the IL-1-responsive D10.G4 cell line also revealed a sixfold increase of IL-1 activity in the macrophage supernatants of staggerer mutant mice [30].
• Cytological compartmentalization in the staggerer cerebellum, as revealed by calbindin immunohistochemistry for Purkinje cells [31].
• Plc beta3 and Rora were labeled by fluorescence in situ hybridization within intact nuclei and their intranuclear, spatial positions quantified by confocal microscopy [32].
• METHODS AND RESULTS: We show that the homozygous staggerer (sg/sg) mutant mouse, which carries a deletion within the nuclear receptor RORalpha gene, develops severe atherosclerosis when maintained on an atherogenic diet [33].

References