| Abstract | It is well known that ?1,6-fucosyltransferase (Fut8) and its products, ?1,6-fucosylated N-glycans, are highly expressed in brain tissue. Recently, we reported that Fut8-knockout mice exhibited multiple behavioral abnormalities with a schizophrenia-like phenotype, suggesting that ?1,6-fucosylation plays important roles in the brain and neuron system. In the present study, we screened several neural cell lines and found that PC12 cells express the highest levels of ?1,6-fucosylation. The knockdown (KD) of Fut8 promoted a significant enhancement of neurite formation and induction of neurofilament expression. Surprisingly, the levels of phospho-SMAD2 were greatly increased in the KD cells. Finally, we found that the activin-mediated signal pathway was essential for these changes in KD cells. Exogenous activin, not TGF-?1, induced neurite outgrowth and phospho-SMAD2. In addition, the ?1,6-fucosylation level on the activin receptors was greatly decreased in KD cells, while the total expression level was unchanged, suggesting that ?1,6-fucosylation negatively regulated activin-mediated signaling. Furthermore, inhibition of activin receptor-mediated signaling or restoration of Fut8 expression rescued cell morphology and phospho-SMAD2 levels, which were enhanced in KD cells. Considering the fact that ?1,6-fucosylation is important for TGF-?-mediated signaling, the results of this study strongly suggest that Fut8 plays a dual role in TGF-?/activin-mediated signaling. |