TACE/ADAM17 is essential for oligodendrocyte development and CNS myelination

Javier Palazuelos, Howard C. Crawford, Michael Klingener, Bingru Sun, Jason Karelis, Elaine W. Raines, Adan Aguirre

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Several studies have elucidated the significance of a disintegrin and metalloproteinase proteins (ADAMs) in PNS myelination, but there is no evidence if they also play a role in oligodendrogenesis and CNS myelination. Our study identifies ADAM17, also called tumor necrosis factor-α converting enzyme (TACE), as a novel key modulator of oligodendrocyte (OL) development and CNS myelination. Genetic deletion of TACE in oligodendrocyte progenitor cells (OPs) induces premature cell cycle exit and reduces OL cell survival during postnatal myelination of the subcortical white matter (SCWM). These cellular and molecular changes lead to deficits in SCWM myelination and motor behavior. Mechanistically, TACE regulates oligodendrogenesis by modulating the shedding of EGFR ligands TGFα and HB-EGF and, consequently, EGFR signaling activation in OL lineage cells. Constitutive TACE depletion in OPs in vivo leads to similar alterations in CNS myelination and motor behavior as to what is observed in the EGFR hypofunctional mouse line EgfrWa2. EGFR overexpression in TACE-deficient OPs restores OL survival and development. Our study reveals an essential function of TACE in oligodendrogenesis, and demonstrates how this molecule modulates EGFR signaling activation to regulate postnatal CNS myelination.

Original languageEnglish (US)
Pages (from-to)11884-11896
Number of pages13
JournalJournal of Neuroscience
Volume34
Issue number36
DOIs
StatePublished - Sep 3 2014

Keywords

  • ADAM17
  • CNS myelination
  • Cell survival
  • EGFR
  • Oligodendrocyte progenitor
  • TACE

ASJC Scopus subject areas

  • Neuroscience(all)

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    Palazuelos, J., Crawford, H. C., Klingener, M., Sun, B., Karelis, J., Raines, E. W., & Aguirre, A. (2014). TACE/ADAM17 is essential for oligodendrocyte development and CNS myelination. Journal of Neuroscience, 34(36), 11884-11896. https://doi.org/10.1523/JNEUROSCI.1220-14.2014