title: Dystroglycan on radial glia end feet is required for pial basement membrane integrity and columnar organization of the developing cerebral cortex.
abstract: Interactions between the embryonic pial basement membrane (PBM) and radial glia (RG) are essential for morphogenesis of the cerebral cortex because disrupted interactions cause cobblestone malformations. To elucidate the role of dystroglycan (DG) in PBM-RG interactions, we studied the expression of DG protein and Dag1 mRNA (which encodes DG protein) in developing cerebral cortex and analyzed cortical phenotypes in Dag1 CNS conditional mutant mice. In normal embryonic cortex, Dag1 mRNA was expressed in the ventricular zone, which contains RG nuclei, whereas DG protein was expressed at the cortical surface on RG end feet. Breaches of PBM continuity appeared during early neurogenesis in Dag1 mutants. Diverse cellular elements streamed through the breaches to form leptomeningeal heterotopia that were confluent with the underlying residual cortical plate and contained variably truncated RG fibers, many types of cortical neurons, and radial and intermediate progenitor cells. Nevertheless, layer-specific molecular expression seemed normal in heterotopic neurons, and axons projected to appropriate targets. Dendrites, however, were excessively tortuous and lacked radial orientation. These findings indicate that DG is required on RG end feet to maintain PBM integrity and suggest that cobblestone malformations involve disturbances of RG structure, progenitor distribution, and dendrite orientation, in addition to neuronal "overmigration."
authors.affiliation: Department of Comparative Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Myshrall
authors.forename: Steven A
authors.initials: SA
authors.lastname: Moore
authors.forename: Adam P
authors.initials: AP
authors.lastname: Ostendorf
authors.forename: Jakob S
authors.initials: JS
authors.lastname: Satz
authors.forename: Tom
authors.initials: T
authors.lastname: Kowalczyk
authors.forename: Huy
authors.initials: H
authors.lastname: Nguyen
authors.forename: Ray A M
authors.initials: RA
authors.lastname: Daza
authors.forename: Charmaine
authors.initials: C
authors.lastname: Lau
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Campbell
authors.forename: Robert F
authors.initials: RF
authors.lastname: Hevner
mesh_terms: D000367:Age Factors; D000818:Animals; D001485:Basement Membrane / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D001973:Bromodeoxyuridine / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002540:Cerebral Cortex / Q000166:cytology* / Q000196:embryology*; D049030:Dystroglycans / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D020287:In Situ Nick-End Labeling; D007381:Intermediate Filament Proteins / Q000172:deficiency; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000378:metabolism; D064231:Nestin; D009457:Neuroglia / Q000166:cytology*; D009474:Neurons / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D013234:Stem Cells / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: C511143:Bcl11b protein, mouse; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D012333:RNA, Messenger; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D049030:Dystroglycans; D001973:Bromodeoxyuridine