Semaphorin3A-induced receptor endocytosis during axon guidance responses is mediated by L1 CAM.
During axon navigation, Semaphorin3A-induced growth cone retraction is correlated with endocytosis. Although its function remains elusive, we showed previously that the cell adhesion molecule of the immunoglobulin super family L1 associates with Neuropilin-1 (NP-1) the Sema3A-binding subunit of the receptor complex and is required for Sema3A to elicit axonal repulsive responses. We report here that upon Sema3A binding to NP-1, L1 and NP-1 are co-internalized through a clathrin-dependent mechanism mediated by L1. We show that in COS7 cells, L1/NP-1 endocytosis is correlated with a cell contraction similar to that observed with the Plexin (Plex)/NP-1 or Plex/NP1/L1 complexes. In neuronal cultures, a L1-mimetic peptide able to switch Sema3A repulsive responses to attraction blocks both endocytosis and growth cone collapse. Similarly, in the COS7 cell model, peptide application prevents both the Sema3-induced L1/NP-1 internalization and cell collapse. These studies demonstrate that the L1/NP-1 complex is able to confer a biological response to Sema3A with L1 mediating receptor internalization following ligand activation. They also reveal that endocytosis controlled by L1/NP-1 cis and trans interactions is pivotal in Sema3A-mediated axon guidance.
Castellani
Valérie
V
Laboratoire de Neurogenèse et Morphogenèse dans le Développement et chez l'Adulte; UMR CNRS 6156, Université de la Méditerranée, IBDM, 13288 Marseilles 9, France.
Falk
Julien
J
Rougon
Geneviève
G
D000818:Animals; D000831:Animals, Newborn; D019556:COS Cells; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002450:Cell Communication / Q000502:physiology; D002478:Cells, Cultured; D002966:Clathrin / Q000378:metabolism; D003463:Cues; D004705:Endocytosis / Q000502:physiology*; D020439:Growth Cones / Q000378:metabolism* / Q000648:ultrastructure; D008024:Ligands; D046911:Macromolecular Substances; D051379:Mice; D009414:Nerve Growth Factors / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009420:Nervous System / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism*; D039942:Neuropilin-1 / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D011485:Protein Binding / Q000502:physiology; D040121:Semaphorin-3A / Q000378:metabolism*
D015815:Cell Adhesion Molecules; D002966:Clathrin; D008024:Ligands; D046911:Macromolecular Substances; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D039842:Neural Cell Adhesion Molecule L1; D010455:Peptides; D040121:Semaphorin-3A; C091529:plexin; D039942:Neuropilin-1