Glial scaffold required for cerebellar granule cell migration is dependent on dystroglycan function as a receptor for basement membrane proteins

Abstract

BackgroundCobblestone lissencephaly is a severe neuronal migration disorder associated with congenital muscular dystrophies (CMD) such as Walker-Warburg syndrome, muscle-eye-brain disease, and Fukuyama-type CMD. In these severe forms of dystroglycanopathy, the muscular dystrophy and other tissue pathology is caused by mutations in genes involved in O-linked glycosylation of alpha-dystroglycan. While cerebellar dysplasia is a common feature of dystroglycanopathy, its pathogenesis has not been thoroughly investigated.ResultsHere we evaluate the role of dystroglycan during cerebellar development. Brain-selective deletion of dystroglycan does not affect overall cerebellar growth, yet causes malformations associated with glia limitans disruptions and granule cell heterotopia that recapitulate phenotypes found in dystroglycanopathy patients. Cerebellar pathology in these mice is not evident until birth even though dystroglycan is lost during the second week of embryogenesis. The severity and spatial distribution of glia limitans disruption, Bergmann glia disorganization, and heterotopia exacerbate during postnatal development. Astrogliosis becomes prominent at these same sites by the time cerebellar development is complete. Interestingly, there is spatial heterogeneity in the glia limitans and granule neuron migration defects that spares the tips of lobules IV-V and VI.ConclusionsThe full spectrum of developmental pathology is caused by loss of dystroglycan from Bergmann glia, as neither granule cell- nor Purkinje cell-specific deletion of dystroglycan results in similar pathology. These data illustrate the importance of dystroglycan function in radial/Bergmann glia, not neurons, for normal cerebellar histogenesis. The spatial heterogeneity of pathology suggests that the dependence on dystroglycan is not uniform.

Malformation of the Posterior Cerebellar Vermis Is a Common Neuroanatomical Phenotype of Genetically Engineered Mice on the C57BL/6 Background

“…In either case, disruption of radial fibers ultimately leads to the failure of granule cells to exit the molecular layer (external granule cell layer) which leads to heterotopia formation by these cells. Lending further support to our model of heterotopia formation, knock-out mice with deletion of molecules affecting leptomeningeal or radial glia integrity such as b1-integrin [47], γ3-laminin [48], and dystroglycan [49, 50] display heterotopia that are nearly identical (but more severe) to those observed in C57BL/6 mice and GE mice on the C57BL/6 background.…”

Comparison of brain MRI findings with language and motor function in the dystroglycanopathies

“…26 Recent work has shown that abnormal glycosylation of a-dystroglycan in Bergman glial cells in the cerebellum similarly results in discontinuity of the glial limitans and cerebellar heterotopia. 27 Mice with reduced or absent DG have developmental brain malformations of variable severity, similar to the spectrum seen in humans. 28,29 Due to the phenotypic variability associated with each gene, several approaches have been used to classify the DGs based on brain imaging or pathology.…”

Single-cell sequencing of human iPSC-derived cerebellar organoids shows recapitulation of cerebellar development

“…A popular method to promote sustained growth of cortical organoids has been the addition of MG to the culture setting, promoting differentiation through exposure to molecules present at the basement membrane (Lancaster et al, 2018). In the cerebellum the ECM-enriched basement membrane is directly below the pial meningeal layer, which provides an anchor point for endfeet of radial processes from VZ precursors and also forms a barrier to migrating neurons (Halfter and Yip, 2014;Nguyen et al, 2013). In both cortical and cerebellar development, these processes provide a scaffold that facilitates neuronal migration and correct layer formation.…”