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.
Doulazmi
Mohamed
M
Université Pierre et Marie Curie-Paris 6, Unité Mixte de Recherche, Neurobiologie des Processus Adaptatifs, Centre National de la Recherche Scientifique, Paris, France. mohamed.doulazmi@snv.jussieu.fr
Capone
Francesca
F
Frederic
Florence
F
Bakouche
Joëlle
J
Boukhtouche
Joëlle
J
Lemaigre-Dubreuil
Yolande
Y
Mariani
Jean
J
D000375:Aging / Q000235:genetics; D000818:Animals; D002452:Cell Count; D016923:Cell Death / Q000235:genetics; D048429:Cell Size; D005260:Female; D005838:Genotype; D006579:Heterozygote; D007150:Immunohistochemistry / Q000379:methods; D008137:Longitudinal Studies; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D011689:Purkinje Cells / Q000166:cytology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D018168:Receptors, Retinoic Acid / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics*
D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; C539739:Rora protein, mouse; D015534:Trans-Activators