title: Netrin 1 and Dcc regulate oligodendrocyte process branching and membrane extension via Fyn and RhoA.
abstract: The molecular mechanisms underlying the elaboration of branched processes during the later stages of oligodendrocyte maturation are not well understood. Here we describe a novel role for the chemotropic guidance cue netrin 1 and its receptor deleted in colorectal carcinoma (Dcc) in the remodeling of oligodendrocyte processes. Postmigratory, premyelinating oligodendrocytes express Dcc but not netrin 1, whereas mature myelinating oligodendrocytes express both. We demonstrate that netrin 1 promotes process extension by premyelinating oligodendrocytes in vitro and in vivo. Addition of netrin 1 to mature oligodendrocytes in vitro evoked a Dcc-dependent increase in process branching. Furthermore, expression of netrin 1 and Dcc by mature oligodendrocytes was required for the elaboration of myelin-like membrane sheets. Maturation of oligodendrocyte processes requires intracellular signaling mechanisms involving Fyn, focal adhesion kinase (FAK), neuronal Wiscott-Aldrich syndrome protein (N-WASP) and RhoA; however, the extracellular cues upstream of these proteins in oligodendrocytes are poorly defined. We identify a requirement for Src family kinase activity downstream of netrin-1-dependent process extension and branching. Using oligodendrocytes derived from Fyn knockout mice, we demonstrate that Fyn is essential for netrin-1-induced increases in process branching. Netrin 1 binding to Dcc on mature oligodendrocytes recruits Fyn to a complex with the Dcc intracellular domain that includes FAK and N-WASP, resulting in the inhibition of RhoA and inducing process remodeling. These findings support a novel role for netrin 1 in promoting oligodendrocyte process branching and myelin-like membrane sheet formation. These essential steps in oligodendroglial maturation facilitate the detection of target axons, a key step towards myelination.
authors.affiliation: Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3A 2B4, Canada.
authors.forename: Sathyanath
authors.initials: S
authors.lastname: Rajasekharan
authors.forename: K Adam
authors.initials: KA
authors.lastname: Baker
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Horn
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Jarjour
authors.forename: Jack P
authors.initials: JP
authors.lastname: Antel
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Kennedy
mesh_terms: D000818:Animals; D048430:Cell Shape / Q000502:physiology; D022081:Cell Surface Extensions / Q000502:physiology*; D002478:Cells, Cultured; D000075389:DCC Receptor; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000502:physiology; D009414:Nerve Growth Factors / Q000235:genetics / Q000502:physiology*; D000075388:Netrin-1; D009836:Oligodendroglia / Q000166:cytology / Q000502:physiology*; D011485:Protein Binding; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal / Q000235:genetics / Q000502:physiology; D020764:cdc42 GTP-Binding Protein / Q000502:physiology; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000502:physiology*
chemical_list: D000075389:DCC Receptor; C501910:Dcc protein, mouse; C501912:Dcc protein, rat; D009414:Nerve Growth Factors; C000617353:Ntn1 protein, mouse; C000617354:Ntn1 protein, rat; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; C495772:Wasl protein, mouse; C495770:Wasl protein, rat; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; D000075388:Netrin-1; D051417:Focal Adhesion Kinase 1; C494960:Fyn protein, mouse; C494961:Fyn protein, rat; D051076:Proto-Oncogene Proteins c-fyn; C496051:Ptk2 protein, mouse; C496052:Ptk2 protein, rat; D020764:cdc42 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein