Working model of abnormal cerebellar development in dystroglycanopathies. In control mice at E14.5 (A), the rhombic lip gives rise to granule cell precursors (GCPs), which migrate across the cerebellar surface to form a secondary zone of neurogenesis, the EGL. Radial glia from the vz extend their endfeet to the cerebellar surface, forming the glia limitans complete with basement membrane. In the nestin-Cre/DG-null mice (B), DG is lost by E14.5 in all cells derived from the neuroepithelium; the cerebellar basement membrane at this time point remains intact. As cells continue to proliferate, the EGL is further divided into two zones: the outer EGL consisting of still-proliferating GCPs, and the inner EGL consisting of post mitotic GCs. GCs from the inner EGL will migrate inward, along radial glia, past the PC layer to settle in the IGL. The cerebellum at P8—the peak of post natal development—is illustrated in panel C. In the nestin-Cre/DG-null mice (D), small breaks at the basement membrane are detectable on the day of birth then exacerbate. A failure of basement membrane assembly, basement membrane maintenance, and/or glial end foot-basement membrane adhesion, result in aberrant radial glia/Bergmann glia organization as the cerebellum grows. Post mitotic GCs from the inner EGL fail to migrate and remain trapped at the cerebellar surface due to lack of glial scaffolds or alterations in the local environment such as astrogliosis (red stellate cells). The EGL ceases to exist toward the end of normal post-natal development (P16, E). In the nestin-Cre/DG-null mice (F), ectopic GCs are prominent at the cerebellar surface where the basement membrane is disrupted and Bergmann glia are highly unorganized. Despite their failure to migrate, these ectopic neurons express markers of differentiated GCs. Reactive gliosis is prominent within these regions of disrupted glia limitans and heterotopic GC.