Back to Search
Start Over
Dysregulation of TGF-β1 receptor activation leads to abnormal lung development and emphysema-like phenotype in core fucose-deficient mice.
- Source :
- Proceedings of the National Academy of Sciences of the United States of America; 11/1/2005, Vol. 102 Issue 44, p15791-15796, 6p
- Publication Year :
- 2005
-
Abstract
- 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<superscript>-/-</superscript> mice showed emphysema-like changes in the lung, verified by a physiological compliance analysis. Biochemical studies indicated that lungs from Fut8<superscript>-/-</superscript> mice exhibit a marked overexpress ion 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<superscript>-/-</superscript> 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<superscript>-/-</superscript> cells can be rescued by reintroducing Fut8 into Fut8<superscript>-/-</superscript> cells. Furthermore, exogenous TGF-β1 potentially rescued emphysema-like phenotype and concomitantly reduced MMP expression in Fut8<superscript>-/-</superscript> 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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00278424
- Volume :
- 102
- Issue :
- 44
- Database :
- Complementary Index
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 19056381
- Full Text :
- https://doi.org/10.1073/pnas.0507375102