Functionally distinct PI 3-kinase pathways regulate myelination in the peripheral nervous system Journal Article
| Authors: | Heller, B. A.; Ghidinelli, M.; Voelkl, J.; Einheber, S.; Smith, R.; Grund, E.; Morahan, G.; Chandler, D.; Kalaydjieva, L.; Giancotti, F.; King, R. H.; Fejes-Toth, A. N.; Fejes-Toth, G.; Feltri, M. L.; Lang, F.; Salzer, J. L. |
| Article 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 α6β 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 lateracting, laminin-integrin-dependent pathway that negatively regulates myelination. © 2014 Heller et al. |
| Keywords: | signal transduction; controlled study; nonhuman; animal cell; enzyme activity; phosphatidylinositol 3 kinase; extracellular matrix; enzyme phosphorylation; rat; western blotting; schwann cell; nerve cell culture; oncogene c myb; serum and glucocorticoid regulated kinase 1; phosphoprotein; myelination; peripheral nervous system; neu differentiation factor; protein s6; myelin sheath; alpha6beta4 integrin; priority journal; article; merosin; n myc downstream regulated gene 1 |
| Journal Title: | Journal of Cell Biology |
| Volume: | 204 |
| Issue: | 7 |
| ISSN: | 0021-9525 |
| Publisher: | Rockefeller University Press |
| Date Published: | 2014-03-31 |
| Start Page: | 1219 |
| End Page: | 1236 |
| Language: | English |
| DOI: | 10.1083/jcb.201307057 |
| PROVIDER: | scopus |
| PMCID: | PMC3971744 |
| PUBMED: | 24687281 |
| DOI/URL: | |
| Notes: | Export Date: 1 May 2014 -- CODEN: JCLBA -- Source: Scopus |
