Multiple phenotypic changes in mice after knockout of the B3gnt5 gene, encoding Lc3 synthase--a key enzyme in lacto-neolacto ganglioside synthesis

B3gnt5 gene knockout mutant mice appeared normal in the embryonic stage and, if they survived delivery, remained normal during early life. However, about 9% developed early-stage growth retardation, 11% died postnatally in less than 2 months, and adults tended to die in 5-15 months, demonstrating splenomegaly and notably enlarged lymph nodes. Without lacto-neolacto series gangliosides, both homozygous and heterozygous mice gradually displayed fur loss or obesity, and breeding mice demonstrated reproductive defects. Furthermore, B3gnt5 gene knockout disrupted the functional integrity of B cells, as manifested by a decrease in B-cell numbers in the spleen, germinal center disappearance, and less efficiency to proliferate in hybridoma fusion.These novel results demonstrate unequivocally that lacto-neolacto series gangliosides are essential to multiple physiological functions, especially the control of reproductive output, and spleen B-cell abnormality. We also report the generation of anti-IgG response against the lacto-series gangliosides 3'-isoLM1 and 3',6'-isoLD1.Gangliosides constitute a large group of sialylated glycosphingolipids (GSLs), which are preferentially (the concentrations intracellularly are most likely higher) expressed on the outer leaf of plasma membranes. The clusters of most negatively charged gangliosides are associated mainly with membranes of either hematopoietic progenitors or stromal cells of a variety of tissues. Functionally, gangliosides influence cell growth and death, probably because they are involved in the glyco-mediated assembling of signaling molecules, such as growth factor receptors or integrins, and cell adhesion molecules and their ligands [1-4], which further modulate the signaling pathway [5,6]. Gangliosides help to determine the microenvironment inside a cell [7]--its physical or chemical properties, local pH, calcium homeostasis, etc. [8], which could enhance or abrogate the biological availability of signaling molecules and