Three-dimensional regulation of radial glial functions by Lis1-Nde1 and dystrophin glycoprotein complexes.
Radial glial cells (RGCs) are distinctive neural stem cells with an extraordinary slender bipolar morphology and dual functions as precursors and migration scaffolds for cortical neurons. Here we show a novel mechanism by which the Lis1-Nde1 complex maintains RGC functions through stabilizing the dystrophin/dystroglycan glycoprotein complex (DGC). A direct interaction between Nde1 and utrophin/dystrophin allows for the assembly of a multi-protein complex that links the cytoskeleton to the extracellular matrix of RGCs to stabilize their lateral membrane, cell-cell adhesion, and radial morphology. Lis1-Nde1 mutations destabilized the DGC and resulted in deformed, disjointed RGCs and disrupted basal lamina. Besides impaired RGC self-renewal and neuronal migration arrests, Lis1-Nde1 deficiencies also led to neuronal over-migration. Additional to phenotypic resemblances of Lis1-Nde1 with DGC, strong synergistic interactions were found between Nde1 and dystroglycan in RGCs. As functional insufficiencies of LIS1, NDE1, and dystroglycan all cause lissencephaly syndromes, our data demonstrated that a three-dimensional regulation of RGC's cytoarchitecture by the Lis1-Nde1-DGC complex determines the number and spatial organization of cortical neurons as well as the size and shape of the cerebral cortex.
Department of Neurology and Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
Ashley S
AS
Pawlisz
Yuanyi
Y
Feng
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000502:physiology*; D000818:Animals; D001485:Basement Membrane / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000196:embryology*; D004195:Disease Models, Animal; D049030:Dystroglycans / Q000378:metabolism*; D016189:Dystrophin / Q000378:metabolism*; D006801:Humans; D054082:Lissencephaly / Q000209:etiology; D054081:Malformations of Cortical Development, Group II / Q000209:etiology; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000502:physiology*; D010641:Phenotype; D049411:Utrophin / Q000378:metabolism
D018797:Cell Cycle Proteins; D016189:Dystrophin; D008869:Microtubule-Associated Proteins; C531336:Nde1 protein, mouse; D049411:Utrophin; D049030:Dystroglycans; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C513190:Pafah1b1 protein, mouse