The regulation of growth and differentiation signales of nerve cells bar sphingoglycolipids.

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To investigate the roles of glycosphingolipids in the nervous system, we have isolated glycosyltransferase genes and manipulated them for the analysis. By remodeling of carbohydrates in cultured neural cells and establishing mutant mice of glycosyltransferase genes based on the homologous recombination, we aimed to analyze the carbohydrate functions in cells and in vivo.The mutant mice lacking GM2/GD2 synthase gene exhibited no marked abnormalities in the morphology of the brain and nerve tissues, but showed functional abnormalities in some analyses such as nerve conductivity and rota-rod test. These mutant mice showed progressive damages in the sensory nerves, motor functions and characteristic pathological degeneration with aging. Reduced sensitivity to pain stimulation, gait disturbance, degeneration in the sciatic nerves, dorsal root ganglia and spinal cords (dorsal horn) were detected. These findings indicated that complex gangliosides are essential in the maintenance of the nerve tissues.On the otherhand, transgenic mice of GM2/GD2 synthase gene showed a shift of ganglioside composition from b-series to a-series, and exhibited some behavior abnormalities and reduced regenerative activity of the damaged hypoglossal nerve. These results suggested that ganglioside compositions should be strictly kept to maintain the intact neural functions.The knock-out mice of GD3 synthase gene were born and grown up without apparent abnormalities. However, abnormal behaviors and muscle weakness were detected in the male mice after 40 weeks after birth. The double knock-out mice of GM2/GD2 synthase and GD3 synthase genes retained only GM3 among gangliosides, and showed neural degeneration and abnormal behaviors in the earlier time than the single mutant mice. Particularly, they showed sudden death at about 12-16 weeks old, suggesting they have novel and serious deffects based on the loss of unknown important functions of glycolipids.