Cis and trans interactions of L1 with neuropilin-1 control axonal responses to semaphorin 3A.
Mutations in the L1 gene induce a spectrum of human neurological disorders due to abnormal development of several brain structures and fiber tracts. Among its binding partners, L1 immunoglobulin superfamily adhesion molecule (Ig CAM) associates with neuropilin-1 (NP-1) to form a semaphorin3A (Sema3A) receptor and soluble L1 converts Sema3A-induced axonal repulsion into attraction. Using L1 constructs containing missense pathological mutations, we show here that this reversion is initiated by a specific trans binding of L1 to NP-1, but not to L1 or other Ig CAMs, and leads to activation of the NO/cGMP pathway. We identified the L1-NP-1-binding site in a restricted sequence of L1 Ig domain 1, as a peptide derived from this region could reverse Sema3A repulsive effects. A pathological L1 missense mutation located in this sequence specifically disrupts both L1-NP-1 complex formation and Sema3A reversion, suggesting that the cross-talk between L1 and Sema3A might participate in human brain development.
Castellani
V
V
Laboratoire de Neurogenèse et Morphogenèse dans le Développement et chez l'Adulte, UMR CNRS 6156, Université de la Méditerranée, IBDM, Parc Scientifique de Luminy, 13288 Marseille cedex 9, France.
De Angelis
E
E
Kenwrick
S
S
Rougon
G
G
D000818:Animals; D001369:Axons / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D051379:Mice; D009154:Mutation; D039842:Neural Cell Adhesion Molecule L1 / Q000235:genetics / Q000378:metabolism*; D039942:Neuropilin-1 / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D040121:Semaphorin-3A / Q000378:metabolism* / Q000494:pharmacology
D039842:Neural Cell Adhesion Molecule L1; D011993:Recombinant Fusion Proteins; D040121:Semaphorin-3A; D039942:Neuropilin-1; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP