Abstract
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.
Original language | English (US) |
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Article number | e1001172 |
Journal | PLoS biology |
Volume | 9 |
Issue number | 10 |
DOIs | |
State | Published - Oct 2011 |
Funding
The authors wish to thank Dr. James Ervasti (University of Minnesota) for Flag-tagged mouse full-length Utrn cDNA as well as a full-length Dystrophin (Dmd) cDNA; Renjie Li for histology assistance; and Dr. Warren Tourtellotte (Northwestern) for muscle histology consultation. Electron microscopy was performed with the help of Lennell Reynolds at Northwestern University Cell Imaging Facility (supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center). We would also like to thank Maria Donoghue (Georgetown University) for comments and suggestions and Andrea Turner and Carina Emery for discussions and reading of the manuscript.
ASJC Scopus subject areas
- General Agricultural and Biological Sciences
- General Biochemistry, Genetics and Molecular Biology
- General Immunology and Microbiology
- General Neuroscience