Date of Degree
PhD (Doctor of Philosophy)
Steven A. Moore
Kevin P. Campbell
Dystroglycanopathies are muscular dystrophies caused by mutations in genes involved the in O-linked glycosylation of alpha-dystroglycan. Severe forms exhibit brain and ocular developmental abnormalities in addition to muscular dystrophy. While cerebellar dysplasia is a common feature of dystroglycanopathy, its pathogenesis has not been thoroughly investigated. Here we evaluate the role of dystroglycan during cerebellar development. Brain-selective deletion of dystroglycan does not affect overall cerebellar growth, but 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 granule cell heterotopia rapidly increase 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. The 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, but not neurons, during cerebellar histogenesis. The spatial heterogeneity of pathology shows that the dependence on dystroglycan is not uniform.
Cognitive deficits are constant features of severe dystroglycanopathies, yet the precise molecular mechanism leading to neuronal dysfunction in these diseases is not known. Here, we show that dystroglycan interaction with dystrophin is required for the normal clustering of a subset of inhibitory synapses in Purkinje neurons. Using mouse models of dystroglycan mutants, we demonstrate that the number of gamma-aminobutyric acid receptor-containing synapses is significantly reduced in the absence of dystroglycan or portions of dystroglycan; a similar result is attained in dystrophin-deficient mice. Finally, we verify that the number of these receptors is retained when dystroglycan and dystrophin are preserved exclusively in Purkinje neurons. Our findings substantiate the notion that brain dystroglycan is important for neuronal function and suggest a molecular mechanism that may underline cognitive impairments in dystroglycanopathies.
cerebellar, development, dystroglycan
ix, 107 pages
Includes bibliographical references (pages 97-107).
Copyright 2013 Huy Nguyen