title: Multiple phenotypic changes in mice after knockout of the B3gnt5 gene, encoding Lc3 synthase--a key enzyme in lacto-neolacto ganglioside synthesis.
abstract: 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.
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA. kuan@duke.edu
authors.forename: Chien-Tsun
authors.initials: CT
authors.lastname: Kuan
authors.forename: Jinli
authors.initials: J
authors.lastname: Chang
authors.forename: Jan-Eric
authors.initials: JE
authors.lastname: Mansson
authors.forename: Jianjun
authors.initials: J
authors.lastname: Li
authors.forename: Charles
authors.initials: C
authors.lastname: Pegram
authors.forename: Pam
authors.initials: P
authors.lastname: Fredman
authors.forename: Roger E
authors.initials: RE
authors.lastname: McLendon
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
mesh_terms: D000505:Alopecia / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001402:B-Lymphocytes / Q000473:pathology; D001483:Base Sequence; D002240:Carbohydrate Sequence; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology; D005260:Female; D005732:Gangliosides / Q000096:biosynthesis* / Q000737:chemistry; D016130:Immunophenotyping; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics* / Q000378:metabolism; D009765:Obesity / Q000235:genetics; D010641:Phenotype; D012098:Reproduction / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D013154:Spleen / Q000002:abnormalities / Q000033:anatomy & histology; D015996:Survival Rate; D014018:Tissue Distribution
chemical_list: D005732:Gangliosides; D007527:Isoenzymes; D017351:N-Acetylglucosaminyltransferases; C067641:lactosylceramide 1,3-N-acetyl-beta-D-glucosaminyltransferase