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: 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, Steven D Shapiro, Carlos Lopez-Otin, Tomoyuki Kuwaki, Masaru Okabe, Koichi Honke, Naoyuki Taniguchi
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 102 Issue 44 Pg. 15791-6 (Nov 01 2005) ISSN: 0027-8424 [Print] United States
• PMID: 16236725 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Transforming Growth Factor beta
• Smad2 Protein
• Smad2 protein, mouse
• Fucose
• Fucosyltransferases
• Glycoprotein 6-alpha-L-fucosyltransferase
• Protein Serine-Threonine Kinases
• Activin Receptors, Type I
• Receptor, Transforming Growth Factor-beta Type I
• Matrix Metalloproteinases

Topics

• Activin Receptors, Type I (metabolism)
• Animals
• Emphysema (etiology)
• Fucose (deficiency)
• Fucosyltransferases (deficiency, genetics)
• Glycosylation
• Lung (growth & development, pathology)
• Matrix Metalloproteinases (biosynthesis)
• Mice
• Mice, Knockout
• Phenotype
• Phosphorylation
• Protein Serine-Threonine Kinases
• Receptor, Transforming Growth Factor-beta Type I
• Receptors, Transforming Growth Factor beta (metabolism)
• Signal Transduction
• Smad2 Protein (metabolism)