LGI1 is a nogo receptor 1 ligand that antagonizes myelin-based growth inhibition

Mutations in leucine-rich glioma inactivated (LGI1) are a genetic cause of autosomal dominant temporal lobe epilepsy with auditoryfeatures. LGI1 is a secreted protein that shares homology with members of the SLIT family, ligands that direct axonal repulsion andgrowth cone collapse, and we therefore considered the possibility that LGI1 may regulate neuronal process extension or growth conecollapse. Here we report that LGI1 does not affect growth directly but instead enhances neuronal growth on myelin-based inhibitorysubstrates and antagonizes myelin-induced growth cone collapse. We show that LGI1 mediates this effect by functioning as a specificNogo receptor 1 (NgR1) ligand that antagonizes the action of myelin-based inhibitory cues. Finally, we demonstrate that NgR1 andADAM22 physically associate to form a receptor complex in which NgR1 facilitates LGI1 binding to ADAM22