Disruption of the nuclear hormone receptor RORα in staggerer mice

Abstract

Homozygous staggerer (sg) mice show a characteristic severe cerebellar ataxia due to a cell-autonomous defect in the development of Purkinje cells. These cells show immature morphology, synaptic arrangement, biochemical properties and gene expression, and are reduced in numbers. In addition, sg heterozygotes show accelerated dendritic atrophy and cell loss, suggesting that sg has a role in mature Purkinje cells. Effects of this mutation on cerebellar development have been studied for 25 years, but its molecular basis has remained unknown. 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. Staggerer mice were found to carry a deletion within the RORalpha gene that prevents translation of the ligand-binding homology domain. We propose a model based on these results, in which RORalpha interacts with the thyroid hormone signalling pathway to induce Purkinje-cell maturation.

Rorα, a pivotal nuclear receptor for Purkinje neuron survival and differentiation: From development to ageing

“…Analyses of these staggerer chimeras demonstrated that the Purkinje cell loss was a direct consequence of the cell-autonomous action of the staggerer mutation (33), which is consistent with the distribution of RORα mRNA and protein in the cerebellum, where only Purkinje cells and interneurones have been shown to express RORα (19,22,34).…”

“…RORα has been detected in many tissues including brain, thymus, skeletal muscle, skin, heart, vessels, liver, lung, gut, kidney tubules, whisker follicles and pancreas (15,(18)(19)(20). In the brain, in situ hybridization and immunohistochemical analyses revealed Rora expression in the cerebellum, in olfactory bulb, hippocampus, thalamus, cerebral cortex (mainly in layer IV), suprachiasmatic nuclei of the hypothalamus and retinal ganglion cells (18,21,22).…”

“…The staggerer mutation has been identified as a deletion within the Rora gene that shifts the reading frame and prevents the translation of the LBD of the RORα protein (19). The strong decrease in Rora sg allelic mRNA (19), together with the similar cerebellar phenotype displayed by both Rora sg/sg and Rora -/-mutants (23), suggests that the staggerer mutation is a null mutation and thus leads to the loss of function of RORα.…”

“…Mutant mice lacking functional RORα protein (18,19) To determine whether the effect of the staggerer mutation was direct (intrinsic) or indirect (extrinsic), staggerer <=> wild-type chimeras were made by aggregating two embryos at the 8-cell stage of development. Analyses of these staggerer chimeras demonstrated that the Purkinje cell loss was a direct consequence of the cell-autonomous action of the staggerer mutation (33), which is consistent with the distribution of RORα mRNA and protein in the cerebellum, where only Purkinje cells and interneurones have been shown to express RORα (19,22,34).…”

Orphan nuclear receptors in drug discovery

“…RORα is also expressed in the spleen, thymus, and macrophages. The initial studies on the in vivo function of RORα came from an animal model known as staggerer mice, which have a deletion in the RORα gene [49]. These mice exhibit ataxic phenotype resulting from a massive neurodegeneration in the cerebellum, which is caused by a developmental defect in Purkinje cells [50].…”