Functionally distinct PI 3-kinase pathways regulate myelination in the peripheral nervous system

Bradley A. Heller, Monica Ghidinelli, Jakob Voelkl, Steven Einheber, Ryan Smith, Ethan Grund, Grant Morahan, David Chandler, Luba Kalaydjieva, Filippo Giancotti, Rosalind H. King, Aniko Naray Fejes-Toth, Gerard Fejes-Toth, Maria Laura Feltri, Florian Lang, James L. Salzer

Research output: Contribution to journalArticlepeer-review

56 Citations (Scopus)

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 alpha 6 beta 4 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. 6. 4 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.

Original languageEnglish
Pages (from-to)1219-1236
Number of pages18
JournalThe Journal of Cell Biology
Volume204
Issue number7
DOIs
Publication statusPublished - 31 Mar 2014

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