title: TACE/ADAM17 is essential for oligodendrocyte development and CNS myelination.
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.
authors.affiliation: Department of Pharmacological Sciences, Centers for Molecular Medicine, Stony Brook University, SUNY, New York 11794.
authors.forename: Javier
authors.initials: J
authors.lastname: Palazuelos
authors.affiliation: Mayo Clinic Cancer Center, Jacksonville, Florida 32224, and.
authors.forename: Howard C
authors.initials: HC
authors.lastname: Crawford
authors.affiliation: Department of Pharmacological Sciences, Centers for Molecular Medicine, Stony Brook University, SUNY, New York 11794.
authors.forename: Michael
authors.initials: M
authors.lastname: Klingener
authors.affiliation: Department of Pharmacological Sciences, Centers for Molecular Medicine, Stony Brook University, SUNY, New York 11794.
authors.forename: Bingru
authors.initials: B
authors.lastname: Sun
authors.affiliation: Department of Pharmacological Sciences, Centers for Molecular Medicine, Stony Brook University, SUNY, New York 11794.
authors.forename: Jason
authors.initials: J
authors.lastname: Karelis
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington 98195.
authors.forename: Elaine W
authors.initials: EW
authors.lastname: Raines
authors.affiliation: Department of Pharmacological Sciences, Centers for Molecular Medicine, Stony Brook University, SUNY, New York 11794, adan.aguirre@stonybrook.edu.
authors.forename: Adan
authors.initials: A
authors.lastname: Aguirre
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D001921:Brain / Q000254:growth & development / Q000378:metabolism* / Q000502:physiology; D002460:Cell Line; D019070:Cell Lineage; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008124:Locomotion; D051379:Mice; D009186:Myelin Sheath / Q000378:metabolism*; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D055495:Neurogenesis; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism*; D016211:Transforming Growth Factor alpha / Q000378:metabolism
chemical_list: C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D016211:Transforming Growth Factor alpha; D066246:ErbB Receptors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse
keywords: ADAM17; CNS myelination; EGFR; TACE; cell survival; oligodendrocyte progenitor