Dysregulation of TGF-beta1 receptor activation leads to abnormal lung development and emphysema-like phenotype in core fucose-deficient mice

• Published in: Proceedings of the National Academy of Sciences - PNAS 2005-11, Vol.102 (44), p.15791-15796
• Main Authors: Wang, Xiangchun, Inoue, Shinya, Gu, Jianguo, Miyoshi, Eiji, Noda, Katsuhisa, Li, Wenzhe, Mizuno-Horikawa, Yoko, Nakano, Miyako, Asahi, Michio, Takahashi, Motoko, Uozumi, Naofumi, Ihara, Shinji, Lee, Seung Ho, Ikeda, Yoshitaka, Yamaguchi, Yukihiro, Aze, Yoshiya, Tomiyama, Yoshiaki, Fujii, Junichi, Suzuki, Keiichiro, Kondo, Akihiro, Shapiro, Steven D, Lopez-Otin, Carlos, Kuwaki, Tomoyuki, Okabe, Masaru, Honke, Koichi, Taniguchi, Naoyuki
• Format: Article
• Language: English
• Subjects: Activin Receptors, Type I - metabolism; Animals; Biochemistry; Cell differentiation; Emphysema; Emphysema - etiology; Fucose - deficiency; Fucosyltransferases - deficiency; Fucosyltransferases - genetics; Genotype & phenotype; Glycoproteins; Glycosylation; Lung - growth & development; Lung - pathology; Matrix Metalloproteinases - biosynthesis; Mice; Mice, Knockout; Phenotype; Phosphorylation; Physiology; Protein-Serine-Threonine Kinases; Receptors, Transforming Growth Factor beta - metabolism; Rodents; Signal Transduction; Smad2 Protein - metabolism
• ISSN: 0027-8424; 1091-6490

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.