The ECM glycoprotein laminin has profound and varied actions on neurons in vitro. Little is known about how laminin's multiple domains and receptor-binding sites interact in determining its overall effects. Here, it is shown that laminin's ability to promote migration of olfactory epithelium neuronal cells maps to distal long arm domain E8 and is mediated by alpha 6 beta 1 integrin. Surprisingly, treatment of laminin with antibodies against its short arms (domains E1' or P1') uncovered a new neuronal migration-promoting activity, mediated by a beta 1 integrin other than alpha 6 beta 1. Laminin treated with anti-short arm antibodies also promoted beta 1 integrin-dependent neurite outgrowth from late embryonic retinal neurons, which are normally unresponsive to laminin. These "antibody-induced" migration and neurite outgrowth activities mapped to laminin's distal long arm, far from the site(s) of antibody binding. Evidence is presented that the induced activities are not actually cryptic in laminin, but are suppressed by an activity that is located in laminin's P1' domain and that may be lacking in the laminin homolog merosin.

Neuronal precursors and Immature neurons of the mouse olfactory epithelium (OE) are motile in vho, and can be stimuiated to migrate and are gulded in vito by the ECM protein lanminin (LN) and its homoiogue merosin (MN). LN and MN are also arti-adhesive, i.e. they cause OE neuronal celis to adhere weakly to substrata that would otherwise be strongly adhesive (Cabf and Lander (1991) J. Cel Biol. 115:779). Investigations Into the domains of laminin responsible for its effects on OE celis have revealed the following: The anti-adhesive activity of LN is highly heat stable and maps to the El' fragment of the molecule. Aithough Integrin at1P1 Is a cell-surface receptor krnown to Interact with this reglon of LN, function-bbcking antibodies directed against this integrin do not Inhibit arntiadhesion. The migration-promoting activity of LN Is dstinct from Its anftadhesive activity, and is not the result of adhesion-altering effects of LN. Migration-prmoting acivity is heat-labile, maps to the E8 fragmert of IN, and can be completely blocked by a monoclonal antibody directed against lntegdn subunit a6. Migration promoted by MN, however, Is only partially blocked by this antibody. Surprisingly, aithough LN is not detectably adhesive for OE neuronal cells, some of its domains are. E8 is weakly adhesive, and a recombinant G-domain (rG) Is strongly adhesive. Adhesion to rG was not dependent on aS-containing integrins, nor could it be blocked by a peptide contained In rG that is thought to represent the binding site of integrin a3p1. Adhesion to rG was blocked, however, by low concentrations of hepardn (<20 pgrn) and by antibodies directed against LIN fragment E3 (which Is contained In rG). These data suggest that neuronal adhesion, anti-adhesion and migration can be independently regulated by distinct domains of LN and distinct receptors.