Previously, we reported that ␣1,6-fucosyltransferase (Fut8)-deficient (Fut8 ؊/؊ ) mice exhibit emphysema-like changes in the lung and severe growth retardation due to dysregulation of TGF-␤1 and EGF receptors and to abnormal integrin activation, respectively. To study the role of ␣1,6-fucosylation in brain tissue where Fut8 is highly expressed, we examined Fut8 ؊/؊ mice using a combination of neurological and behavioral tests. ␣1,6-Fucosyltransferase (Fut8) 2 catalyzes the transfer of a fucose residue from GDP-fucose to position 6 of the innermost GlcNAc residue to form ␣1,6-fucose in hybrid and complex N-linked oligosaccharides of glycoproteins as shown in Fig. 1 (1). ␣1,6-Fucosylated glycoproteins are widely distributed in mammalian tissues, especially in the brain (2). In fact, the majority of N-glycans present in mouse brain tissue are ␣1,6-fucosylated (3). We recently investigated the physiological functions of ␣1,6-fucose by using Fut8-deficient (Fut8 Ϫ/Ϫ ) mice (4). Fut8 Ϫ/Ϫ mice showed severe growth retardation. They also suffered from emphysema-like changes in their lungs that appeared to be due to a lack of ␣1,6-fucosylation of the transforming growth factor-␤1 (TGF-␤1) receptor, which consequently resulted in dysregulation of TGF-␤1 receptor activation and signaling (4), and down-regulation of expression of vascular endothelial cell growth factor receptor-2 (5). In addition, deletion of the core fucose from the IgG1 molecule reportedly enhances antibody-dependent cellular cytotoxicity activity by 50 -100-fold. This result indicates that ␣1,6-fucose is an important sugar chain in terms of antibody-dependent cellular cytotoxicity activity (6). Moreover, the loss of ␣1,6-fucosylation down-regulates both EGF receptor-mediated cell signaling pathways (7) and integrin ␣3␤1-mediated cell adhesion (8). Taken together, these results suggest that ␣1,6-fucose plays a key role in regulating important physiological functions via modification of functional proteins.Complex N-glycans are required for the development of the embryo, and the complete lack of N-glycans in GnT-I-deficient mice is lethal with defects in neural tube formation (9). These observations suggest that high-mannose N-glycans are insufficient for normal ontogeny. On the other hand, restriction of N-glycan branching to the formation of only hybrid structures by GnT-II inactivation in mice results in a very low rate of * This work was supported by Scientific Research Grants-in-aid 21370059 (to J. G.) and 22590071 (to T. F.) from the Japan Society for the Promotion of Science and the Academic Frontier Project for Private Universities from the Ministry of Education, Culture, Sports, Science and Technology of Japan. 1 To whom correspondence should be addressed. Tel.: 81-22-727-0216; Fax:81-22-727-0078; E-mail: jgu@tohoku-pharm.ac.jp.2 The abbreviations used are: Fut8, ␣1,6-fucosyltransferase; PPI, prepulse inhibition; TGF-␤1, transforming growth factor-␤1; GnT-III, N-acetylglucosaminyltransferase III; GnT-V, N-acetylglucosaminyltransferase V; 5-HT, 5-h...