Neuronal migration defects in cerebellum of the Largemyd mouse are associated with disruptions in Bergmann glia organization and delayed migration of granule neurons.

The Large gene encodes a putative glycosyltransferase that is required for normal glycosylation of dystroglycan, and defects in either Large or dystroglycan cause abnormal neuronal migration. The mechanism for this effect is not fully understood. This study analyzes the Largemyd mouse cerebellum during postnatal cerebellar development. Large is shown to be expressed most strongly in the Bergmann glial cells and Purkinje cells throughout cerebellar development, which is similar to what is known for dystroglycan expression. Discontinuities of the pial surface of the developing Largemyd mouse cerebellum correlate with disruption of the normal organization of the external granule cell layer and Bergmann glial fibers. At early time points, granule neurons express differentiation markers normally, both temporally and spatially, and show no defects in neurite outgrowth in in vitro assays. However, granule neuron migration is delayed within the external granule and molecular layers, resulting in granule neurons undergoing their intrinsically programmed differentiation in inappropriate locations. Consequently, cells expressing mature granule neuron markers become stranded within these layers. The cause of the less efficient migration is likely due to both physical disruption of the glial-guide scaffolding, as well as to suboptimal neuronal-glial guide interactions during migration.