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.