Age-related phenotypes in the staggerer mouse expand the RORalpha nuclear receptor's role beyond the cerebellum.

The homozygous mutant mouse staggerer (RORa(sg)/RORa(sg)), was initially described as ataxic, due to the presence of massive neurodegeneration in the cerebellum [Science 136 (1962) 610]. The identification of the widely expressed Retinoic acid receptor-related Orphan Receptor, NR1F1 (RORalpha) gene as the site of mutation in the staggerer mouse has led to great progress in understanding the molecular basis of its phenotype in recent years [Nature 379 (1996) 736]. RORalpha is a transcription factor, belonging to the nuclear receptor superfamily, for which no natural ligand has yet been identified. Mice engineered for the disruption of the gene encoding RORalpha display the same cerebellar atrophic phenotype as the staggerer mouse [Proc. Natl. Acad. Sci. USA 95 (1998) 3960]. More recently, it has been shown that the mutation is semi-dominant, as heterozygous animals display an increased loss of Purkinje cells with age. Furthermore, a number of additional phenotypes outside the nervous system have recently been identified. These include a greater susceptibility to atherosclerosis [Circulation 15 (1998) 2738], immunodeficiencies linked to the overexpression of inflammatory cytokines [J. Neurochem. 58 (1992) 192], abnormalities in the formation and maintenance of bone tissue [Proc. Natl. Acad. Sci. USA 97 (2000) 9197] and changes in muscle differentiation [Nucleic Acids Res. 27 (1999) 411]. Thus, RORalpha has been directly linked to a number of age-related pathologies of great medical interest.