CEREBELLAR PURKINJE CELL LOSS IN HETEROZYGOUSRORA^+/−MICE: A LONGITUDINAL STUDY

Abstract

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.

Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia

“…41 Heterozygous Rora þ/À mice present with a comparable phenotype, although they display a late onset of neuronal loss and reduced phenotypic severity. 42 Further studies will be required to understand the precise molecular mechanisms of p.Gly92Ala and p.Lys94Arg to account for their apparent toxic effects. We speculate that these changes in the DNA binding domain might hamper access of WT RORa to its natural target sites (Figure S3B), thereby leading to a phenotype resembling to the staggerer and Rora À/À homozygous mutants.…”

RORα Attenuates Wnt/β-Catenin Signaling by PKCα-Dependent Phosphorylation in Colon Cancer

“…Thus far, many studies have focused mainly on the analysis of cerebellar defects (Gold et al, 2003). Approximately 50% of the Sg mice die shortly after weaning, which makes studying RORa function with Sg mice very difficult (Doulazmi et al, 2006). Our studies have widened the spectrum of the roles of RORa to the negative regulation of tumor progression and proliferation in colon cancer using a combination of a proteomic approach and molecular mechanism approach in cell culture model and in clinical tissue samples of patients with colorectal carcinoma.…”

Mild Cerebellar Neurodegeneration of Aged Heterozygous PCD Mice Increases Cell Fusion of Purkinje and Bone Marrow-Derived Cells

“…Our data suggest that PC death in +/ pcd mice is rare and occurs as isolated events, since PC loss spreads slowly from the vermis to the cerebellar hemispheres. Gradual PC apoptosis has been observed in other neurodegenerative models involving heterozygous animals with recessive mutations; these include both in vitro (37) and in vivo (10) examples. In these models, cell death was usually detected in old animals, suggesting that it is an age-related effect (6,10,11,30).…”

“…Gradual PC apoptosis has been observed in other neurodegenerative models involving heterozygous animals with recessive mutations; these include both in vitro (37) and in vivo (10) examples. In these models, cell death was usually detected in old animals, suggesting that it is an age-related effect (6,10,11,30). Thus, gene silencing of the wild-type allele or any other age-related alteration of the genome may provide a possible explanation for the observed apoptotic PC death subpopulation in heterozygous animals (16).…”