The cell adhesion molecule L1 is important for peripheral nerve development. Mice lacking the 6th Ig domain of L1 (L1-6D mice) lose L1 homophilic binding and RGD dependent LI-integrin binding [Itoh,K., Cheng, L., Kamei, Y., Fushiki, S., Kamiguchi, H., Gutwein, P.,Stoeck, A., Arnold, B., Altevogt, P., Lemmon, V., 2004. Brain development in mice lacking Li-L homophilic adhesion. J. Cell Biol.165, 145-154]. We examined the ultrastructure of sciatic nerves from L1-6D at postnatal day 7 and 8 weeks. Unmyelinated axons frequently detached at the edge of Schwann cells, and naked axons were observed. Myelin was thinner in L1-6D and abnormal, multiple axons wrapped in a single myelin sheath were routinely observed. Previous work has shown that L1 on axons interacts with a heterophilic binding partner on Schwann cells to facilitate normal peripheral nerve formation. Taken together, it is likely that L1 on axons binds integrins on Schwann cells, resulting in interactions between axons and Schwann cells that are essential for ensheathment and myelination.