Nervous System & Sugar Chain

Functional Role of the HNK-1 Carbohydrate in the Nervous System

 The HNK-1 carbohydrate is characteristically expressed on a series of cell adhesion molecules, and the expression is spatially and temporally regulated during the development of the nervous system, suggesting that the HNK-1 carbohydrate plays an important role in the formation of the neural network1).

Glucuronyltransferase(s) and sulfotransferase(s) are key enzymes for this carbohydrate biosynthesis, because the structure of the HNK-1 carbohydrate is a sulfated trisaccharide, HSO3-3GlcAb1-3Gal1-4GlcNAc, and the inner structure, Gal1-4GlcNAc, is commonly found on various glycoproteins and glycolipids. Two glucuronyltransferases (GlcAT-P and GlcAT-S) and one sulfotransferase (HNK-1 ST) have so far been cloned (Fig. 1). The expression of GlcAT-P mRNA is higher than that of GlcAT-S in the nervous system. We generated mice with a targeted deletion of the GlcAT-P gene to demonstrate that the HNK-1 carbohydrate is required for higher functions of the brain2).
Fig.1 HNK-1 carbohydrate biosynthesis

GlcAT-P was thought to be specific to the glycoprotein acceptors. However, the glucuronyltransferase activity of GlcAT-P gene-deficient mice toward the glycolipid acceptor disappeared almost completely as well as the activity toward the glycoprotein acceptor. Almost all the HNK-1 carbohydrate also disappeared in GlcAT-P gene-deficient mouse brain (Fig. 2-a), suggesting that GlcAT-P is the most predominant glucuronyltransferase responsible for the biosynthesis of the HNK-1 carbohydrate in brain.
Fig.2 Phenotype of GlcAT-P gene-deficient mice

The HNK-1 carbohydrate is highly expressed during the period corresponding to synaptogenesis. We analyzed LTP in the CA1 region to examine the effect of HNK-1 carbohydrate deficiency on synaptic plasticity. High-frequency stimulation of afferent fibers gave rise to LTP of excitatory synaptic transmission in wild type mice, while the magnitude of LTP in the GlcAT-P gene-deficient mice was significantly lower than that in wild-type mice (Fig. 2-b). In view of the reduced LTP, two types of spatial learning tests were carried out. In the Morris water maze test, the time taken to reach the hidden platform (escape latency) was significantly longer for the GlcAT-P gene-deficient mice than wild-type mice (Fig. 2-c). In the water-filled multiple T-maze task, the GlcAT-P gene-deficient mice showed increased escape latencies to the goal arm compared to wild-type mice. These results indicate that the HNK-1 carbohydrate plays an important role in synaptic plasticity and spatial memory formation.

The HNK-1 ST gene-deficient mice was also generated and analyzed independently. Basal synaptic transmission in pyramidal cells in the CA1 region of the hippocampus was increased and LTP evoked by theta-burst stimulation was reduced in the HNK-1 ST gene-deficient mice. In the water maze test, HNK-1 ST gene-deficient mice showed impaired spatial learning. These lines of evidence clearly indicate that the HNK-1 carbohydrate plays an essential role in the higher functions of the brain.

Recently, Jeffries et al. (2003) mapped both chromosome breakpoints of a balanced t(6;11)(q14.2;q25) chromosome translocation that segregates with a schizophrenia-like psychosis3). The chromosome 11 breakpoint is situated close to the telomere and the closest gene is GlcAT-P. As GlcAT-P-deficient mice show defects in hippocampal LTP and in spatial memory formation, the above authors propose that the translocation causes a positional effect on GlcAT-P, affecting expression levels.
Shogo Oka (Graduate School of Pharmaceutical Sciences, Kyoto University)
References (1) Kleene R, Schachner M: Glycans and neural cell interactions. Nature Rev. Neurosci., 5, 195-208, 2004
(2) Yamamoto S, Oka S, Inoue M, Shimuta M, Manabe T, Takahashi H, Miyamoto M, Asano M, Sakagami J, Sudo K, Iwakura Y, Ono K, Kawasaki T: Mice deficient in nervous system-specific carbohydrate epitope HNK-1 exhibit impaired synaptic plasticity and spatial learning. J. Biol. Chem., 277, 27227-27231, 2002
(3) Jeffries AR, Mungall AJ, Dawson E, Halls K, Langford CF, Murray RM, Dunham I, Powell JF: -1,3-Glucuronyltransferase-1 gene implicated as a candidate for a schizophrenia-like psychosis through molecular analysis of a balanced translocation. Mol. Psychiatry, 8, 654-663, 2003
Links GP-A01 Biological Functions of the HNK-1 Carbohydrate Epitope (Shogo Oka)
  PG-B05 Functional Roles of Protein Tyrosine Phosphatase (PTP /RPTP )(Masaharu Noda)
Jan. 24, 2005

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