Pattern development in the mammalian cerebellum

The cerebellum is patterned into intricate arrays of stripes, both in the adult and during embryogenesis. The complex migration of Purkinje cells during development combined with the temporal expression gap observed between most early- and late-onset Purkinje cell patterns make it difficult to understand the genealogy of cerebellar patterning. This thesis addresses the issue. To start, I present novel neurogranin expression data showing it is the first Purkinje cell parasagittal marker whose pattern spans the gap between early and late-onset patterns. I use this pattern as a reference to compare the expression patterns of other early onset markers---calbindin (CaBP) and heat shock protein (HSP)25---to the prototypical late onset pattern marker zebrin II. From these expression patterns a high-resolution expression map was built of the developing anterior cerebellar vermis. The map identifies at least 4 Purkinje cell phenotypes and six distinct antigenic cluster compartments revealing that late-onset stripes arise from defined perinatal Purkinje cell clusters. By combining BrdU birthdating with the antigenic map I confirm that the Purkinje cells in a particular perinatal antigenic compartment share birthdates. I tested the validity of this genealogical map by using a mutant---the cerebellar deficient folia (cdf) mouse---that exhibits a zebrin II-immunonegative Purkinje cell ectopia in the adult. I reasoned that these cells fail to disperse during development and therefore a defined subset, consistent with the predictions of the antigenic map, would be ectopic in the perinatal cdf cerebellum. Indeed, the data indicates that a specific population of Purkinje cells expressing HSP25, among other markers, is ectopic in the perinatal cerebellum. Finally, I examined mice homozygous null for one of the two Reelin receptors---ApoER2 and VLDLR---to explore the mechanisms of Purkinje cell dispersal. The data showed that receptor deletion impeded the dispersal of specific parasagittal and transverse subsets of Purkinje cells. Taken together the data support a model whereby Purkinje cells acquire a mediolateral phenotype at or shortly following their birth in the neuroepithelium and that their identity is preserved as they migrate to form adult stripes.