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

Artikel i vetenskaplig tidskrift
Författare Chien-Tsun Kuan
Jinli Chang
Jan-Eric Månsson
Jianjun Li
Charles Pegram
Pam Fredman
Roger E. McLendon
Darell D. Bigner
Publicerad i BMC Developmental Biology
Volym 10
Sidor art. 114
ISSN 1471-213X
Publiceringsår 2010
Publicerad vid Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi
Sidor art. 114
Språk en
Länkar dx.doi.org/10.1186/1471-213X-10-114
Ämnesord myelin-associated glycoprotein, nervous-system, in-vivo, lactotetraose series, gm3, antibodies, glycosphingolipids, model, brain, regeneration
Ämneskategorier Neurokemi

Sammanfattning

Background Ganglioside biosynthesis occurs through a multi-enzymatic pathway which at the lactosylceramide step is branched into several biosynthetic series. Lc3 synthase utilizes a variety of galactose-terminated glycolipids as acceptors by establishing a glycosidic bond in the beta-1,3-linkage to GlcNaAc to extend the lacto- and neolacto-series gangliosides. In order to examine the lacto-series ganglioside functions in mice, we used gene knockout technology to generate Lc3 synthase gene B3gnt5-deficient mice by two different strategies and compared the phenotypes of the two null mouse groups with each other and with their wild-type counterparts. Results 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. Conclusions 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.

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