Dysregulation of TGF-β1 receptor activation leads to abnormal lung development and emphysema-like phenotype in core fucose-deficient mice

Xiangchun Wang, Shinya Inoue, Jianguo Gu, Eiji Miyoshi, Katsuhisa Noda, Wenzhe Li, Yoko Mizuno-Horikawa, Miyako Nakano, Michio Asahi, Motoko Takahashi, Naofumi Uozumi, Shinji Ihara, Seung Ho Lee, Yoshitaka Ikeda, Yukihiro Yamaguchi, Yoshiya Aze, Yoshiaki Tomiyama, Junichi Fujii, Keiichiro Suzuki, Akihiro KondoSteven D. Shapiro, Carlos Lopez-Otin, Tomoyuki Kuwaki, Masaru Okabe, Koichi Honke, Naoyuki Taniguchi*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    377 Citations (Scopus)


    The core fucosylation (α1,6-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 α1,6-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-β1 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-β1 receptor activation and signaling, as assessed by TGF-β1 binding assays and Smad2 phosphorylation analysis. We also show that these TGF-β1 receptor defects found in Fut8-/- cells can be rescued by reintroducing Fut8 into Fut8-/- cells. Furthermore, exogenous TGF-β1 potentially rescued emphysema-like phenotype and concomitantly reduced MMP expression in Fut8-/- lung. We propose that the lack of core fucosylation of TGF-β1 receptors is crucial for a developmental and progressive/destructive emphysema, suggesting that perturbation of this function could underlie certain cases of human emphysema.

    Original languageEnglish
    Pages (from-to)15791-15796
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Issue number44
    Publication statusPublished - 1 Nov 2005


    • Fucosylation
    • Glycobiology
    • Matrix metalloproteinase


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