Knock-out Mice of Glycolipid-glycosyltransferase Genes

 Glycolipids are a group of amphopathic molecules consisting of lipids named ceramide and carbohydrates. They exist abundantly in the nervous system of vertebrates, but are also present broadly in other tissues and cells. Depending on the sugar that attaches to the nonreduced end of lactosylceramide, Gal-Glc-Cer, three synthetic pathways leading to the formation of lacto-series (neolacto-series), globo-series , and ganglio-series have been defined. Above all, the ganglio-series glycolipids contain many sialic acids , and are designted ganglyosides. They have been considered to be impotant in the functions of the nervous system.

A number of functions of gangliosides, such as neurotrophic factor-like actions, have been reported. However, it was difficult to learn the actual roles of gangliosides, because many studies were conducted by the observation of effects of exogenous gangliosides on cells and tissues. Recently, glycosyltransferase genes have been cloned and their availability has enabled us to remodel the carbohydrate structures in the levels of cultured cells and experimental animals, resulting in the elucidation of novel functions of carbohydrates. In particular, gene knock-out is expected to be a unique approach to obtaining definite results, although there are some disadvantages.

Among glycosyltransferase genes responsible for the synthesis of glycolipids, GM2/GD2 synthase and galactosyltransferase (Gal-Cer synthase) have been knocked out to date. The former was generated by our group, and the latter was established by K. Suzuki and W. Stoffel, independently. In GM2/GD2 synthase knock-out mice, no morphological changes or apparent abnormal behaviors were observed. Only significantly lowered nerve conductivity was detected. These results were much less than expected. One possible explanation is that the remaining simpler gangliosides may compensate for the functions of the complex gangliosides. The fact that regeneration after nerve injury was markedly suppressed and degeneration of the peripheral nerves took place in the knock-out mice may indicate that complex gangliosides are critical for the maintenance and repair of nerve tissue. The Most serious phenotype in the knock-out mice was male infertility due to spermatogenesis, giving rise to the idea that gangliosides may be involved in testosterone transport. Moreover, dysfunctions in T lymphocytes were also reported. All these results indicate that gangliosides are involved in the systemic regulatory systems.

In the knock-out mice of Gal-Cer synthase, termor, ataxia, and deficits in nerve conduction were observed, indicating that galactosylceramide and its sulfated derivatives are impotant in the maintenance and stabilization of myelin. Therefore, these mutant mice can not survive for a long time after birth.

If knock-out mice of other glycosyltransferase genes become available, the precise roles of the individual carbohydrate structures can be demonstrated.
Koichi Furukawa
(Nagoya University School of Medicne, Department of Biochemistry II)
References (1) Takamiya K, Yamamoto A, Furukawa K, Yamashiro S, Shin M, Okada M, Fukumoto S, Haraguchi M, Takeda N, Fujimura K, Sakae M, Kishikawa M, Shiku H, Furukawa K, Aizawa S: Mice with disrupted GM2/GD2 synthase gene lack complex gangliosides but exhibit only subtle defects in their nervous system. Proc. Natl. Acad. Sci. USA 93, 10662-10667, 1996.
(2) Takamiya K, Yamamoto A, Furukawa K, Zhao J, Yamashiro S, Okada M, Haraguchi M, Shin M, Kishikawa M, Shiku H, Aizawa S, Furukawa K: Complex gangliosides are essential in spermatogenesis of mice : Possible roles in the transport of testosterone. Proc. Natl. Acad. Sci. USA 95, 12147-12152, 1998.
(3) Coetzee T, Fujita N, Dupree J, Shi R, Blight A, Suzuki K, Suzuki K, Popko B: Myelination in the absence of galactocerebroside and sulfatide: normal structure with abnormal function and regional instability. Cell 86, 209-219, 1996.
(4) Bosio A, Binczek E, Stoffel W: Functional breakdown of the lipid bilayer of the myelin membrane in central and peripheral nervous system by disrupted galactocerebroside synthesis. Proc. Natl. Acad. Sci. USA 93, 13280-13285, 1996.
Jun. 15, 1999

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