Functionally distinct PI 3-kinase pathways regulate myelination in the peripheral nervous system
| Autor: | Gerard Fejes-Toth, Aniko Naray Fejes-Toth, Florian Lang, Steven Einheber, James L. Salzer, Grant Morahan, Maria Laura Feltri, Luba Kalaydjieva, Ethan M. Grund, Bradley A. Heller, Monica Ghidinelli, Ryan Smith, Jakob Voelkl, Rosalind H.M. King, David Chandler, Filippo G. Giancotti |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Neuregulin-1
Integrin Gene Expression Cell Cycle Proteins Mice Transgenic Protein Serine-Threonine Kinases Immediate early protein Article Immediate-Early Proteins Receptors Laminin Mice Phosphatidylinositol 3-Kinases Peripheral Nervous System medicine Animals Integrin-linked kinase Axon Neuregulin 1 Phosphorylation Protein kinase A Research Articles Cells Cultured Myelin Sheath Mice Inbred BALB C Ribosomal Protein S6 biology urogenital system Integrin beta4 Intracellular Signaling Peptides and Proteins Cell Biology Coculture Techniques 3. Good health Cell biology Extracellular Matrix Rats medicine.anatomical_structure nervous system Ribosomal protein s6 biology.protein Laminin Schwann Cells Signal transduction Protein Processing Post-Translational Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | The Journal of Cell Biology |
| ISSN: | 1540-8140 0021-9525 |
| Popis: | Functionally and spatially distinct PI 3-K pathways act either early to promote myelination downstream of axonal Neuregulin1 or late to inhibit myelination downstream of α6β4 integrin and Sgk1. 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. |
| Databáze: | OpenAIRE |
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