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-tota l depletion of granule cells in the anterior lobe of the cerebellum, a s 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 g ene is unknown. This issue is addressed by examining cerebella from ad ult chimeras in which both the genotype and phenotype of individual ce lls are marked and examined, From this analysis, three novel observati ons are made, First, genotypically mea/mea Purkinje cells and glial ce lls exhibit normal morphologies in the cerebella of chimeric mice indi cating that the mea gene acts extrinsically to these two cell populati ons, Second, few genotypically mea/mea granule cells are present in th e anterior lobe or, unexpectedly, in the posterior lobe, These finding s indicate that the mea gene acts intrinsically to the granule cell or its precursors to perturb their development, Third, there are near-no rmal numbers of cerebellar granule cells in the chimeric cerebellum, T his result suggests that mea/mea cells are out-competed and subsequent ly replaced by an increased cohort of wild-type granule cells resultin g from an upregulation of wild-type granule cells in the chimeric envi ronment. We propose that the wild-type allele of the mea gene is criti cal for the developmental progression of the early granule cell neurob last.