title: Dysregulation of TGF-beta1 receptor activation leads to abnormal lung development and emphysema-like phenotype in core fucose-deficient mice.
abstract: The core fucosylation (alpha1,6-fucosylation) of glycoproteins is widely distributed in mammalian tissues, and is altered under pathological conditions. To investigate physiological functions of the core fucose, we generated alpha1,6-fucosyltransferase (Fut8)-null mice and found that disruption of Fut8 induces severe growth retardation and death during postnatal development. Histopathological analysis revealed that Fut8(-/-) mice showed emphysema-like changes in the lung, verified by a physiological compliance analysis. Biochemical studies indicated that lungs from Fut8(-/-) mice exhibit a marked overexpression of matrix metalloproteinases (MMPs), such as MMP-12 and MMP-13, highly associated with lung-destructive phenotypes, and a down-regulation of extracellular matrix (ECM) proteins such as elastin, as well as retarded alveolar epithelia cell differentiation. These changes should be consistent with a deficiency in TGF-beta1 signaling, a pleiotropic factor that controls ECM homeostasis by down-regulating MMP expression and inducing ECM protein components. In fact, Fut8(-/-) mice have a marked dysregulation of TGF-beta1 receptor activation and signaling, as assessed by TGF-beta1 binding assays and Smad2 phosphorylation analysis. We also show that these TGF-beta1 receptor defects found in Fut8(-/-) cells can be rescued by reintroducing Fut8 into Fut8(-/-) cells. Furthermore, exogenous TGF-beta1 potentially rescued emphysema-like phenotype and concomitantly reduced MMP expression in Fut8(-/-) lung. We propose that the lack of core fucosylation of TGF-beta1 receptors is crucial for a developmental and progressive/destructive emphysema, suggesting that perturbation of this function could underlie certain cases of human emphysema.
authors.affiliation: Department of Biochemistry, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
authors.forename: Xiangchun
authors.initials: X
authors.lastname: Wang
authors.forename: Shinya
authors.initials: S
authors.lastname: Inoue
authors.forename: Jianguo
authors.initials: J
authors.lastname: Gu
authors.forename: Eiji
authors.initials: E
authors.lastname: Miyoshi
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Noda
authors.forename: Wenzhe
authors.initials: W
authors.lastname: Li
authors.forename: Yoko
authors.initials: Y
authors.lastname: Mizuno-Horikawa
authors.forename: Miyako
authors.initials: M
authors.lastname: Nakano
authors.forename: Michio
authors.initials: M
authors.lastname: Asahi
authors.forename: Motoko
authors.initials: M
authors.lastname: Takahashi
authors.forename: Naofumi
authors.initials: N
authors.lastname: Uozumi
authors.forename: Shinji
authors.initials: S
authors.lastname: Ihara
authors.forename: Seung Ho
authors.initials: SH
authors.lastname: Lee
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Aze
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Tomiyama
authors.forename: Junichi
authors.initials: J
authors.lastname: Fujii
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Suzuki
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kondo
authors.forename: Steven D
authors.initials: SD
authors.lastname: Shapiro
authors.forename: Carlos
authors.initials: C
authors.lastname: Lopez-Otin
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kuwaki
authors.forename: Masaru
authors.initials: M
authors.lastname: Okabe
authors.forename: Koichi
authors.initials: K
authors.lastname: Honke
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Taniguchi
mesh_terms: D030201:Activin Receptors, Type I / Q000378:metabolism*; D000818:Animals; D004646:Emphysema / Q000209:etiology*; D005643:Fucose / Q000172:deficiency*; D005647:Fucosyltransferases / Q000172:deficiency / Q000235:genetics; D006031:Glycosylation; D008168:Lung / Q000254:growth & development* / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D005643:Fucose; D005647:Fucosyltransferases; C020559:Glycoprotein 6-alpha-L-fucosyltransferase; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; D020782:Matrix Metalloproteinases