title: β2 and γ3 laminins are critical cortical basement membrane components: ablation of Lamb2 and Lamc3 genes disrupts cortical lamination and produces dysplasia.
abstract: Cortical development is dependent on the timely production and migration of neurons from neurogenic sites to their mature positions. Mutations in several receptors for extracellular matrix (ECM) molecules and their downstream signaling cascades produce dysplasia in brain. Although mutation of a critical binding site in the gene that encodes the ECM molecule laminin γ1 (Lamc1) disrupts cortical lamination, the ECM ligand(s) for many ECM receptors have not been demonstrated directly in the cortex. Several isoforms of the heterotrimeric laminins, all containing the β2 and γ3 chain, have been isolated from the brain, suggesting they are important for CNS function. Here, we report that mice homozygous null for the laminin β2 and γ3 chains exhibit cortical laminar disorganization. Mice lacking both of these laminin chains exhibit hallmarks of human cobblestone lissencephaly (type II, nonclassical): they demonstrate severe laminar disruption; midline fusion; perturbation of Cajal-Retzius cell distribution; altered radial glial cell morphology; and ectopic germinal zones. Surprisingly, heterozygous mice also exhibit laminar disruption of cortical neurons, albeit with lesser severity. In compound null mice, the pial basement membrane is fractured, and the distribution of a key laminin receptor, dystroglycan, is altered. These data suggest that β2 and γ3-containing laminins play an important dose-dependent role in development of the cortical pial basement membrane, which serves as an attachment site for Cajal-Retzius and radial glial cells, thereby guiding neural development.
authors.affiliation: Department of Anatomy and Cellular Biology, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Radner
authors.forename: Charles
authors.initials: C
authors.lastname: Banos
authors.forename: Galina
authors.initials: G
authors.lastname: Bachay
authors.forename: Yong N
authors.initials: YN
authors.lastname: Li
authors.forename: Dale D
authors.initials: DD
authors.lastname: Hunter
authors.forename: William J
authors.initials: WJ
authors.lastname: Brunken
authors.forename: Kathleen T
authors.initials: KT
authors.lastname: Yee
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000378:metabolism* / Q000473:pathology; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007797:Laminin / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D055495:Neurogenesis / Q000235:genetics*
chemical_list: C504220:Lamc3 protein, mouse; D007797:Laminin; C058783:laminin beta2