Essential role of alpha 6 integrins in cortical and retinal lamination.

Extracellular matrix (ECM) is believed to play important roles in many aspects of nervous system development [1]. The laminins are ECM glycoproteins expressed in neural tissues and are potent stimulators of neurite outgrowth in vitro [1-3]. Genetic approaches using Drosophila and Caenorhabditis elegans have demonstrated a role for laminin and a laminin receptor in vivo in axon pathfinding and fasciculation, respectively [4,5]. In higher organisms, however, the role of laminins in the development of the nervous system is poorly understood. Integrins alpha 6 beta 1 and alpha 6 beta 4 are major laminin receptors. A role for the alpha 6 integrin in neurulation has been reported in amphibians [6]. We previously described mice lacking integrin alpha 6; these mice died at birth with severe skin blistering [7]. Detailed analyses of integrin alpha 6-/- mice reported here revealed abnormalities in the laminar organization of the developing cerebral cortex and retina. Ectopic neuroblastic outgrowths were found on the brain surface and in the vitreous body in the eye. Alterations of laminin deposition were found in mutant brains. Thus, this study provides evidence for an essential role of integrin-laminin interactions in the proper development of the nervous system. These observations are particularly significant given the recent report that human patients suffering from epidermolysis bullosa can carry mutations in ITGA6, the gene encoding the alpha 6 integrin chain [8,9].