Cortical deficiency of laminin gamma1 impairs the AKT/GSK-3beta signaling pathway and leads to defects in neurite outgrowth and neuronal migration.
Laminins have dramatic and varied actions on neurons in vitro. However, their in vivo function in brain development is not clear. Here we show that knockout of laminin gamma1 in the cerebral cortex leads to defects in neuritogenesis and neuronal migration. In the mutant mice, cortical layer structures were disrupted, and axonal pathfinding was impaired. During development, loss of laminin expression impaired phosphorylation of FAK and paxillin, indicating defects in integrin signaling pathways. Moreover, both phosphorylation and protein levels of GSK-3beta were significantly decreased, but only phosphorylation of AKT was affected in the mutant cortex. Knockout of laminin gamma1 expression in vitro, dramatically inhibited neurite growth. These results indicate that laminin regulates neurite growth and neuronal migration via integrin signaling through the AKT/GSK-3beta pathway, and thus reveal a novel mechanism of laminin function in brain development.
Chen
Zu-Lin
ZL
Laboratory of Neurobiology and Genetics, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
Haegeli
Véronique
V
Yu
Huaxu
H
Strickland
Sidney
S
D000818:Animals; D001921:Brain / Q000196:embryology / Q000254:growth & development; D002465:Cell Movement; D002540:Cerebral Cortex / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D004622:Embryo, Mammalian; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D016023:Integrins / Q000378:metabolism; D007797:Laminin / Q000172:deficiency* / Q000502:physiology; D051379:Mice; D008817:Mice, Mutant Strains; D016501:Neurites / Q000648:ultrastructure*; D009474:Neurons / Q000502:physiology* / Q000648:ultrastructure; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction
D016023:Integrins; D007797:Laminin; C089141:laminin gamma 1; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3