Bace1 processing of NRG1 type III produces a myelin-inducing signal but is not essential for the stimulation of myelination

Viktorija Velanac, Tilmann Unterbarnscheidt, Wilko Hinrichs, Maike N Gummert, Tobias M Fischer, Moritz J Rossner, Amelia Trimarco, Veronica Brivio, Carla Taveggia, Michael Willem, Christian Haass, Wiebke Möbius, Klaus-Armin Nave, Markus H Schwab

Research output: Contribution to journalArticlepeer-review

63 Citations (Scopus)

Abstract

Myelin sheath thickness is precisely adjusted to axon caliber, and in the peripheral nervous system, neuregulin 1 (NRG1) type III is a key regulator of this process. It has been proposed that the protease BACE1 activates NRG1 dependent myelination. Here, we characterize the predicted product of BACE1-mediated NRG1 type III processing in transgenic mice. Neuronal overexpression of a NRG1 type III-variant, designed to mimic prior cleavage in the juxtamembrane stalk region, induces hypermyelination in vivo and is sufficient to restore myelination of NRG1 type III-deficient neurons. This observation implies that the NRG1 cytoplasmic domain is dispensable and that processed NRG1 type III is sufficient for all steps of myelination. Surprisingly, transgenic neuronal overexpression of full-length NRG1 type III promotes hypermyelination also in BACE1 null mutant mice. Moreover, NRG1 processing is impaired but not abolished in BACE1 null mutants. Thus, BACE1 is not essential for the activation of NRG1 type III to promote myelination. Taken together, these findings suggest that multiple neuronal proteases collectively regulate NRG1 processing.

Original languageEnglish
Pages (from-to)203-17
Number of pages15
JournalGlia
Volume60
Issue number2
DOIs
Publication statusPublished - Feb 2012

Keywords

  • Amyloid Precursor Protein Secretases
  • Animals
  • Aspartic Acid Endopeptidases
  • Cell Membrane
  • Coculture Techniques
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation
  • Myelin Sheath
  • Neuregulin-1
  • Peptide Hydrolases
  • Primary Cell Culture
  • Protein Processing, Post-Translational
  • Protein Structure, Tertiary
  • Signal Transduction
  • Journal Article
  • Research Support, Non-U.S. Gov't

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