Cerebellar purkinje cell loss in heterozygous rora+/- mice: a longitudinal study.

The staggerer (sg) mutation is a spontaneous deletion in the Rora gene that prevents the translation of the ligand-binding domain (LBD), leading to the loss of RORalpha activity. The homozygous Rorasg/sg mutant mouse, whose most obvious phenotype is ataxia associated with cerebellar degeneration, also displays a variety of other phenotypes. The heterozygous Rora+/sg is able to develop a cerebellum that is qualitatively normal but which suffers a significant loss of cerebellar neuronal cells with advancing age. A truncated protein synthesized by the mutated allele may play a role both in Rorasg/sg and Rora+/sg. To determine the effects during life span of true haplo-insufficiency of the RORalpha protein, derived from the invalidation of the gene, we compared the evolution of Purkinje cell numbers in heterozygous Rora knock-out males (Rora+/-) and in their wild-type counterparts from 1 to 24 months of age. We also compared the evolution of Purkinje cell (PC) numbers in Rora+/- and Rora+/sg males from 1 to 9 months. The main finding is that in Rora+/- mice, for which only one-half the normal amount of protein is produced, the deficit was established as early as 1 month and did not change during the animals' adult lifespans. Thus, the effects of aging on PC number were apparent much earlier in Rora+/- than in Rora+/sg, although at 24 months of age the degrees of deficit were similar.