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 Kondo & 6 others Steven D. Shapiro, Carlos Lopez-Otin, Tomoyuki Kuwaki, Masaru Okabe, Koichi Honke, Naoyuki Taniguchi*

*Corresponding author for this work

Research output: Contribution to journalArticle

290 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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