Learning/memory impairment and reduced expression of the HNK-1 carbohydrate in beta4-galactosyltransferase-II-deficient mice.
The glycosylation of glycoproteins and glycolipids is important for central nervous system development and function. Although the roles of several carbohydrate epitopes in the central nervous system, including polysialic acid, the human natural killer-1 (HNK-1) carbohydrate, alpha2,3-sialic acid, and oligomannosides, have been investigated, those of the glycan backbone structures, such as Galbeta1-4GlcNAc and Galbeta1-3GlcNAc, are not fully examined. Here we report the generation of mice deficient in beta4-galactosyltransferase-II (beta4GalT-II). This galactosyltransferase transfers Gal from UDP-Gal to a nonreducing terminal GlcNAc to synthesize the Gal beta1-4GlcNAc structure, and it is strongly expressed in the central nervous system. In behavioral tests, the beta4GalT-II(-/-) mice showed normal spontaneous activity in a novel environment, but impaired spatial learning/memory and motor coordination/learning. Immunohistochemistry showed that the amount of HNK-1 carbohydrate was markedly decreased in the brain of beta4GalT-II(-/-) mice, whereas the expression of polysialic acid was not affected. Furthermore, mice deficient in glucuronyltransferase (GlcAT-P), which is responsible for the biosynthesis of the HNK-1 carbohydrate, also showed impaired spatial learning/memory as described in our previous report, although their motor coordination/learning was normal as shown in this study. Histological examination showed abnormal alignment and reduced number of Purkinje cells in the cerebellum of beta4GalT-II(-/-) mice. These results suggest that the Galbeta1-4GlcNAc structure in the HNK-1 carbohydrate is mainly synthesized by beta4GalT-II and that the glycans synthesized by beta4GalT-II have essential roles in higher brain functions, including some that are HNK-1-dependent and some that are not.
Yoshihara
Toru
T
Division of Transgenic Animal Science, Advanced Science Research Center, Kanazawa University, Kanazawa 920-8640, Japan.
Sugihara
Kazushi
K
Kizuka
Yasuhiko
Y
Oka
Shogo
S
Asano
Masahide
M
D000818:Animals; D018959:CD57 Antigens / Q000096:biosynthesis* / Q000235:genetics; D002241:Carbohydrates / Q000096:biosynthesis* / Q000235:genetics; D005690:Galactose / Q000378:metabolism; D005700:Galactosyltransferases; D007858:Learning; D051379:Mice; D018345:Mice, Knockout; D011689:Purkinje Cells / Q000201:enzymology* / Q000473:pathology; D012794:Sialic Acids / Q000096:biosynthesis* / Q000235:genetics
D018959:CD57 Antigens; D002241:Carbohydrates; D012794:Sialic Acids; C021319:polysialic acid; D005700:Galactosyltransferases; D005690:Galactose