title: The activation of ezrin-radixin-moesin proteins is regulated by netrin-1 through Src kinase and RhoA/Rho kinase activities and mediates netrin-1-induced axon outgrowth.
abstract: The receptor Deleted in Colorectal Cancer (DCC) mediates the attractive response of axons to the guidance cue netrin-1 during development. On netrin-1 stimulation, DCC is phosphorylated and induces the assembly of signaling complexes within the growth cone, leading to activation of cytoskeleton regulators, namely the GTPases Rac1 and Cdc42. The molecular mechanisms that link netrin-1/DCC to the actin machinery remain unclear. In this study we seek to demonstrate that the actin-binding proteins ezrin-radixin-moesin (ERM) are effectors of netrin-1/DCC signaling in embryonic cortical neurons. We show that ezrin associates with DCC in a netrin-1-dependent manner. We demonstrate that netrin-1/DCC induces ERM phosphorylation and activation and that the phosphorylation of DCC is required in that context. Moreover, Src kinases and RhoA/Rho kinase activities mediate netrin-1-induced ERM phosphorylation in neurons. We also observed that phosphorylated ERM proteins accumulate in growth cone filopodia, where they colocalize with DCC upon netrin-1 stimulation. Finally, we show that loss of ezrin expression in cortical neurons significantly decreases axon outgrowth induced by netrin-1. Together, our findings demonstrate that netrin-1 induces the formation of an activated ERM/DCC complex in growth cone filopodia, which is required for netrin-1-dependent cortical axon outgrowth.
authors.affiliation: Department of Anatomy and Cell Biology, McGill University, Montreal H3A 2B2, PQ, Canada.
authors.forename: Judith
authors.initials: J
authors.lastname: Antoine-Bertrand
authors.forename: Atefeh
authors.initials: A
authors.lastname: Ghogha
authors.forename: Vilayphone
authors.initials: V
authors.lastname: Luangrath
authors.forename: Fiona K
authors.initials: FK
authors.lastname: Bedford
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lamarche-Vane
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D002490:Central Nervous System / Q000196:embryology* / Q000378:metabolism; D002540:Cerebral Cortex / Q000196:embryology / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism; D000075389:DCC Receptor; D047108:Embryonic Development / Q000235:genetics*; D020439:Growth Cones / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D000075388:Netrin-1; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D011554:Pseudopodia / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*; D000099149:Ezrin
chemical_list: D003598:Cytoskeletal Proteins; D000075389:DCC Receptor; D008565:Membrane Proteins; D008840:Microfilament Proteins; D046912:Multiprotein Complexes; D009414:Nerve Growth Factors; D000075388:Netrin-1; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; D020742:rhoA GTP-Binding Protein; D019061:src-Family Kinases; D000099149:Ezrin; C501909:DCC protein, human; C000617351:NTN1 protein, human; C000617354:Ntn1 protein, rat; C066737:RHOA protein, human; C071058:moesin; C071776:radixin