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^1,2. These cells show immature morphology, synaptic arrangement, biochemical properties and gene expression, and are reduced in numbers^3–12. In addition, sg heterozygotes show accelerated dendritic atrophy and cell loss¹³, 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 RORα, a member of the nuclear hormone-receptor superfamily. Staggerer mice were found to carry a deletion within the RORα gene that prevents translation of the ligand-binding homology domain. We propose a model based on these results, in which RORα interacts with the thyroid hormone signalling pathway to induce Purkinje-cell maturation.