meander tail acts intrinsic to granule cell precursors to disrupt cerebellar development: analysis of meander tail chimeric mice.

The murine mutation meander tail (gene symbol: mea) causes a near-total depletion of granule cells in the anterior lobe of the cerebellum, as well as aberrantly located Purkinje cells with misoriented dendrites and radial glia with stunted processes. Whether one, two or all three of these cell types is the primary cellular target(s) of the mutant gene is unknown. This issue is addressed by examining cerebella from adult chimeras in which both the genotype and phenotype of individual cells are marked and examined. From this analysis, three novel observations are made. First, genotypically mea/mea Purkinje cells and glial cells exhibit normal morphologies in the cerebella of chimeric mice indicating that the mea gene acts extrinsically to these two cell populations. Second, few genotypically mea/mea granule cells are present in the anterior lobe or, unexpectedly, in the posterior lobe. These findings indicate that the mea gene acts intrinsically to the granule cell or its precursors to perturb their development. Third, there are near-normal numbers of cerebellar granule cells in the chimeric cerebellum. This result suggests that mea/mea cells are out-competed and subsequently replaced by an increased cohort of wild-type granule cells resulting from an upregulation of wild-type granule cells in the chimeric environment. We propose that the wild-type allele of the mea gene is critical for the developmental progression of the early granule cell neuroblast.