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The Jackson Laboratory Mouse Genome Informatics database ( currently lists 446 spontaneous neurological mutant alleles, many of which have been annotated with molecular mechanism. These mutant mice have provided fundamental knowledge regarding the pathways critical for the development and function of the cerebellum which have also translated to other CNS regions and have advanced our understanding of the pathogenesis of human neurological disease ( Grüsser-Cornehls and Bäurle, 2001 Hirano, 2006 Meisler et al., 1997). Many classical spontaneous neurological mutants exhibit cerebellar dysfunction or ataxia ( Sidman et al., 1965).

Fine mapping of the tippy mutation to a 2.1MB region of distal chromosome 9, which does not encompass any gene previously implicated in cerebellar development or neuronal degeneration, confirms that the tippy mutation identifies novel biology and gene function. The constellation of Purkinje cell dendritic malformation and degeneration phenotypes in tippy mutants is unique and has not been reported in any other neurologic mutant. Furthermore, we hypothesize that the Purkinje cell axonal pathology together with disruptions in the balance of climbing fiber and parallel fiber Purkinje cell input in the cerebellar cortex underlie the ataxic phenotype in these mice. The data suggest that the Purkinje neurons are a primary target of the tippy mutation. However, decreased ESPC amplitudes were observed in response to parallel fiber stimulation and correlated well with anatomical evidence for patchy dark cell degeneration of Purkinje cell dendrites in the molecular layer. Moderate anatomical abnormalities of climbing fiber innervation of tippy mutant Purkinje cells were not associated with changes in climbing fiber-EPSC amplitudes. Although the cerebellum shows grossly normal foliation, tippy mutants display a complex cerebellar Purkinje cell phenotype consisting of abnormal dendritic branching with immature spine features and patchy, non-apoptotic cell death that is associated with widespread dystrophy and degeneration of the Purkinje cell axons throughout the white matter, the cerebellar nuclei and the vestibular nuclei. Homozygous tippy mutant mice are small, ataxic and die around weaning. This study represents the first detailed analysis of the spontaneous neurological mouse mutant, tippy, uncovering its unique cerebellar phenotype.

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