The community effect and Purkinje cell migration in the cerebellar cortex: analysis of scrambler chimeric mice

The Disabled-1 protein in mouse is known to be an intercellular signaling component of the Reelin molecular pathway that subserves neuronal migration in several structures in the brain and spinal cord. The scrambler mutant mouse, which is phenotypically identical to the reeler mouse, is due to a mutation in the disabled-1 gene (Howell et al., 1997; Sheldon et al., 1997). The Purkinje cells of the cerebellum express Disabled-1 and experience a massive failure of migration in the scrambler mutant mouse (Howell et al., 1997; Sheldon et al., 1997; Gallagher et al., 1998; Rice et al., 1998). We sought to define the developmental basis of this mutation by studying the Purkinje cell population in experimental mouse aggregation chimeras using a cell marker that permitted the identification of neurons derived from the mutant lineage. We found that a genetically normal component to the environment cannot assist scrambler mutant Purkinje cells in the migratory process. However, the presence of a mutant component to the environment can cause the ectopia of wild-type Purkinje cells. There appears to be a linear relationship between the percentage of the cerebellum that is genetically mutant and the number of wild-type Purkinje cells that express a mutant phenotype. These studies point to the interplay between cell-intrinsic and cell-extrinsic properties in the migration of neurons to form laminated structures during CNS development.