THE ARG-GLY-ASP MOTIF IN THE CELL-ADHESION MOLECULE L1 PROMOTES NEURITE OUTGROWTH VIA INTERACTION WITH ALPHA(V)BETA(3) INTEGRIN

The cell adhesion molecule L1 is a potent inducer of neurite outgrowth and it has been implicated in X-linked hydrocephalus and related neur ological disorders. To investigate the mechanisms of neurite outgrowth stimulated by L1, attempts were made to identify the neuritogenic sit es in L1. Fusion proteins containing different segments of the extrace llular region of L1 were prepared and different neuronal cells were as sayed on substrate-coated fusion proteins. Interestingly, both immunog lobulin (Ig)-like domains 2 and 6 (Ig2, Ig6) promoted neurite outgrowt h from dorsal root ganglion cells, whereas neural retinal cells respon ded only to Ig2. L1 Ig2 contains a previously identified homophilic bi nding site, whereas L1 Ig6 contains an Arg-Gly-Asp (RGD) sequence. The neuritogenic activity of Ig6 was abrogated by mutations in the RGD si te. The addition of RGD-containing peptides also inhibited the promoti on of neurite outgrowth from dorsal root ganglion cells by glutathione S-transferase-IgG, implicating the involvement of an integrin. The mo noclonal antibody LM609 against alpha(v) beta(3) integrin, but not an anti-beta(1) antibody, inhibited the neuritogenic effects of Ig6. Thes e data thus provide the first evidence that the RGD motif in L1 Ig6 is capable of promoting neurite outgrowth via interaction with the alpha (v) beta(3) integrin on neuronal cells.