Homozygous mutant mice such as staggerer (sg/sg) or reeler (rl/rl) exhibit a marked ataxia associated with an atrophic cerebellum during the first postnatal weeks and a reduced number of Purkinje cells, the deficit reaching about 75% in sg/sg and 50% in rl/rl as compared to age- and sex-matched mice from the same strain background. These two mutations are classically viewed as recessive, but we have recently shown that heterozygous staggerer (+/sg) mice exhibit a progressive and age-related loss of Purkinje cells between 3 and 12 months of age, despite their apparent clinical normality (Shojaeian-Zanjani et al., 1992). In the present study, we have investigated whether a similar cell loss exists in the cerebellum of heterozygous +/rl mice. The number of Purkinje cells was counted in serial parasagittal sections of the cerebellum of +/rl and their +/+ littermates at 3, 16 and 26 months of age. Our results reveal a 16% deficit in the number of Purkinje cells in 3-month-old +/rl and a 24% one in 16-month-old animals: surprisingly this deficit is only present in the +/rl males, while the females are spared. These results suggest that the reeler gene (D'Arcangelo et al., 1995) exerts its effect on Purkinje cell number in a gender-specific fashion in heterozygous mutant mice.

Abstract:RORα (Retinoid-related Orphan Receptor) is a transcription factor belonging to the superfamily of nuclear receptors. The spontaneous staggerer (sg) mutation, which consists of a deletion in the Rora ge ne, has been shown to cause the loss of function of the RORα protein. The total loss of RORα expression leads to cerebellar developmental defects, particularly to a dramatic decreased survival of Purkinje cells and an early block in the differentiation process. This review focuses on recent studies which position RORα as a pivotal factor controlling Purkinje cell survival and differentiation, from development to ageing.

The staggerer mutation causes dysgenesis of the cerebellar cortex in the homozygous mutant (Rorasg/Rorasg). The mutation acts intrinsically within the Purkinje cells (PCs), leading to cytological abnormalities and a severe deficit in the number of these cells. In contrast, in the heterozygous staggerer (Rora+/Rorasg), the cytoarchitecture of the cerebellar cortex appears to be normal, but quantitative studies have revealed a significant loss of cerebellar neurons with advancing age. In the heterozygous reeler (+/rl), another mutant presenting a PC loss with age, we have found that only males were affected (Hadj‐Sahraoui et al., 1996). In the present study, we have investigated whether a similar gender effect exists in the heterozygous staggerer during life span. PCs were counted on cerebellar sagittal sections in male and female Rora+/Rorasg and in their Rora+/Rora+ littermates at 1, 3, 9, 13, 18, and 24 months of age. In the Rora+/Rora+, the number of PCs remained stable until 18 months, but there was a 25% significant loss in 24‐ month‐old mice of both genders. During life span, Rora+/Rora+ males had slightly more PC than females. In the Rora+/Rorasg of both genders, the deficit in PC number was similar at 13 months but it appeared earlier in males, beginning between 1 and 3 months, and was aggravated regularly up to 13 months. By contrast, the decline was delayed and more abrupt in Rora+/Rorasg females, from a value still normal at 9 months to its maximal extent at 13 months. In view of these results, the heterozygous (Rora+/Rorasg) mouse offers an interesting model to test the interaction between sex, age, and genetic background on the development and maintenance of cerebellar neuronal populations. J. Comp. Neurol. 411:267–273, 1999. © 1999 Wiley‐Liss, Inc.

No abstract