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Cis and trans interactions of L1 with neuropilin‐1 control axonal responses to semaphorin 3A
Author(s) -
Castellani V.,
De Angelis E.,
Kenwrick S.,
Rougon G.
Publication year - 2002
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/cdf645
Subject(s) - semaphorin , sema3a , biology , missense mutation , neuropilin 1 , mutation , plexin , microbiology and biotechnology , receptor , genetics , gene , cancer research , vascular endothelial growth factor , vegf receptors
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.