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

为了研究神经鞘糖脂在神经系统中的作用，我们分离了糖基转移酶基因，并对其进行了分析。通过改造培养的神经细胞中的碳水化合物，建立基于同源重组的糖基转移酶基因突变小鼠，以分析细胞内和活体中的碳水化合物功能。缺失GM2/GD2合成酶基因的突变小鼠在脑和神经组织的形态上没有明显的异常，但在神经传导和转杆试验等分析中出现了功能异常。这些突变的小鼠表现出感觉神经、运动功能的进行性损害，并随着年龄的增长而出现特征性的病理变性。坐骨神经、背根神经节和脊髓(背角)对疼痛刺激的敏感度降低，步态紊乱，变性。另一方面，GM2/GD2合酶基因转基因小鼠表现出神经节苷脂成分从b系列向A系列的转变，并表现出一些行为异常和受损舌下神经再生活性的降低。提示神经节苷脂成分应严格保存，以维持完整的神经功能。GD3合酶基因敲除小鼠在出生和成长过程中均无明显异常。但在出生后40周，雄性小鼠出现异常行为和肌肉无力。GM2/GD2合酶和GD3合酶基因双基因敲除小鼠在神经节苷脂中仅保留GM3，且较单突变小鼠更早出现神经退行性变和行为异常。特别是，它们在12-16周龄时突然死亡，表明它们具有基于糖脂未知重要功能丧失的新的和严重的影响。

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.