Molecular Studies of Brain Malformations

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DESCRIPTION (provided by applicant): Disorders of neuronal migration during brain development result in lissencephaly-type cortical dysplasia. The clinical manifestations of muscle-eye-brain (MEB) disease in the brain involve polymicrogyria caused by neuronal ectopia in the leptomeninges that presumably result from over-migration during development. The genetic basis of MEB disease is null mutations in POMGnT1 encoding a glycosyltransferase involved in O-mannose-type glycosylation of proteins. The cellular and molecular mechanisms of POMGnT 1 deficiency leading to defective neuronal migration are unknown. Genetic analyses of other neuronal migration disorders have identified filamin 1, LIS 1 and doublecortin as key regulators of neuronal migration. Their involvement in cell movement is readily understandable, as they are actin binding or microtubule-associated proteins. The involvement of POMGnT1 in neuronal migration is puzzling because it is an enzyme. It will remain puzzling until its substrates are identified. The overall hypothesis is that alpha-dystroglycan is a key substrate of POMGnT1, such that its glycosylation by POMGnT1 is essential for interactions between radial glia and the brain surface basement membrane. Disrupted interactions in the absence of such glycosylation lead to gross morphological changes in the basement membrane, the marginal zone Cajal-Retzius cells, and the radial glia, resulting in overmigration of neurons. To directly test this hypothesis, a mouse model of MEB disease will be generated. Whether POMGnT1 modifies alpha-dystroglycan and the biological functions of such modifications will be determined. The cellular and molecular effects of POMGnT1 deficiency on radial glia and basement membrane interaction and on neuronal migration will be examined. In addition, other potential candidate glycoproteins modified by POMGnT1 will be identified by a proteomic approach. These studies will provide insight into the cellular and molecular pathogenesis of disrupted protein O-mannosyl glycosylation leading to neuronal migration disorders and on the basic functions of mannosyl glycans in mammalian development.