title: Functionally distinct PI 3-kinase pathways regulate myelination in the peripheral nervous system.
abstract: The PI 3-kinase (PI 3-K) signaling pathway is essential for Schwann cell myelination. Here we have characterized PI 3-K effectors activated during myelination by probing myelinating cultures and developing nerves with an antibody that recognizes phosphorylated substrates for this pathway. We identified a discrete number of phospho-proteins including the S6 ribosomal protein (S6rp), which is down-regulated at the onset of myelination, and N-myc downstream-regulated gene-1 (NDRG1), which is up-regulated strikingly with myelination. We show that type III Neuregulin1 on the axon is the primary activator of S6rp, an effector of mTORC1. In contrast, laminin-2 in the extracellular matrix (ECM), signaling through the α6β4 integrin and Sgk1 (serum and glucocorticoid-induced kinase 1), drives phosphorylation of NDRG1 in the Cajal bands of the abaxonal compartment. Unexpectedly, mice deficient in α6β4 integrin signaling or Sgk1 exhibit hypermyelination during development. These results identify functionally and spatially distinct PI 3-K pathways: an early, pro-myelinating pathway driven by axonal Neuregulin1 and a later-acting, laminin-integrin-dependent pathway that negatively regulates myelination.
authors.affiliation: Neuroscience Institute and 2 Departments of Neuroscience and Physiology and Neurology, NYU Langone Medical Center, New York, NY 10016.
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Heller
authors.forename: Monica
authors.initials: M
authors.lastname: Ghidinelli
authors.forename: Jakob
authors.initials: J
authors.lastname: Voelkl
authors.forename: Steven
authors.initials: S
authors.lastname: Einheber
authors.forename: Ryan
authors.initials: R
authors.lastname: Smith
authors.forename: Ethan
authors.initials: E
authors.lastname: Grund
authors.forename: Grant
authors.initials: G
authors.lastname: Morahan
authors.forename: David
authors.initials: D
authors.lastname: Chandler
authors.forename: Luba
authors.initials: L
authors.lastname: Kalaydjieva
authors.forename: Filippo
authors.initials: F
authors.lastname: Giancotti
authors.forename: Rosalind H
authors.initials: RH
authors.lastname: King
authors.forename: Aniko Naray
authors.initials: AN
authors.lastname: Fejes-Toth
authors.forename: Gerard
authors.initials: G
authors.lastname: Fejes-Toth
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Feltri
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
authors.forename: James L
authors.initials: JL
authors.lastname: Salzer
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D005109:Extracellular Matrix / Q000378:metabolism; D015870:Gene Expression; D017874:Immediate-Early Proteins / Q000378:metabolism; D039663:Integrin beta4 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009186:Myelin Sheath / Q000502:physiology*; D020890:Neuregulin-1 / Q000378:metabolism; D017933:Peripheral Nervous System / Q000166:cytology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017474:Receptors, Laminin / Q000378:metabolism; D038601:Ribosomal Protein S6 / Q000378:metabolism; D012583:Schwann Cells / Q000378:metabolism; D015398:Signal Transduction; D000099184:Serum-Glucocorticoid Regulated Kinases; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D039663:Integrin beta4; D047908:Intracellular Signaling Peptides and Proteins; D007797:Laminin; D020890:Neuregulin-1; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D017474:Receptors, Laminin; D038601:Ribosomal Protein S6; D000099184:Serum-Glucocorticoid Regulated Kinases; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C490581:Nrg1 protein, mouse