title: Distinct functions of glial and neuronal dystroglycan in the developing and adult mouse brain.
abstract: Cobblestone (type II) lissencephaly and mental retardation are characteristic features of a subset of congenital muscular dystrophies that include Walker-Warburg syndrome, muscle-eye-brain disease, and Fukuyama-type congenital muscular dystrophy. Although the majority of clinical cases are genetically undefined, several causative genes have been identified that encode known or putative glycosyltransferases in the biosynthetic pathway of dystroglycan. Here we test the effects of brain-specific deletion of dystroglycan, and show distinct functions for neuronal and glial dystroglycan. Deletion of dystroglycan in the whole brain produced glial/neuronal heterotopia resembling the cerebral cortex malformation in cobblestone lissencephaly. In wild-type mice, dystroglycan stabilizes the basement membrane of the glia limitans, thereby supporting the cortical infrastructure necessary for neuronal migration. This function depends on extracellular dystroglycan interactions, since the cerebral cortex developed normally in transgenic mice that lack the dystroglycan intracellular domain. Also, forebrain histogenesis was preserved in mice with neuron-specific deletion of dystroglycan, but hippocampal long-term potentiation was blunted, as is also the case in the Largemyd mouse, in which dystroglycan glycosylation is disrupted. Our findings provide genetic evidence that neuronal dystroglycan plays a role in synaptic plasticity and that glial dystroglycan is involved in forebrain development. Differences in dystroglycan glycosylation in distinct cell types of the CNS may contribute to the diversity of dystroglycan function in the CNS, as well as to the broad clinical spectrum of type II lissencephalies.
authors.affiliation: Howard Hughes Medical Institute, and Department of Molecular Physiology, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, Iowa City, Iowa 52242, USA.
authors.forename: Jakob S
authors.initials: JS
authors.lastname: Satz
authors.forename: Adam P
authors.initials: AP
authors.lastname: Ostendorf
authors.forename: Shangwei
authors.initials: S
authors.lastname: Hou
authors.forename: Amy
authors.initials: A
authors.lastname: Turner
authors.forename: Hajime
authors.initials: H
authors.lastname: Kusano
authors.forename: Jane C
authors.initials: JC
authors.lastname: Lee
authors.forename: Rolf
authors.initials: R
authors.lastname: Turk
authors.forename: Huy
authors.initials: H
authors.lastname: Nguyen
authors.forename: Susan E
authors.initials: SE
authors.lastname: Ross-Barta
authors.forename: Steve
authors.initials: S
authors.lastname: Westra
authors.forename: Toshinori
authors.initials: T
authors.lastname: Hoshi
authors.forename: Steven A
authors.initials: SA
authors.lastname: Moore
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Campbell
mesh_terms: D000818:Animals; D001921:Brain / Q000002:abnormalities / Q000254:growth & development* / Q000502:physiology*; D001923:Brain Chemistry / Q000235:genetics / Q000502:physiology; D049030:Dystroglycans / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004594:Electrophysiology; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005455:Fluorescent Antibody Technique; D016259:Genes, myc / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D006624:Hippocampus / Q000502:physiology; D006849:Hydrocephalus / Q000235:genetics / Q000473:pathology; D007381:Intermediate Filament Proteins / Q000235:genetics; D017774:Long-Term Potentiation / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics; D064231:Nestin; D009457:Neuroglia / Q000378:metabolism / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D005904:Glial Fibrillary Acidic Protein; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D049030:Dystroglycans