title: Beta4-galactosyltransferase-5 is a lactosylceramide synthase essential for mouse extra-embryonic development.
abstract: Glycosphingolipids (GSLs) are important for various biological functions in the nervous system, the immune system, embryogenesis and in other tissues and processes. Lactosylceramide (LacCer), which is synthesized from glucosylceramide (GlcCer) by LacCer synthase, is a core structure of GSLs, including gangliosides. LacCer synthase was reported to be synthesized by the beta4-galactosyltransferase-6 (beta4GalT-6) gene in the rat brain. However, the existence of another LacCer synthase gene was shown in cultured cells lacking beta4GalT-6. Here, we report that LacCer synthase is mainly synthesized by the beta4GalT-5 gene during early mouse embryogenesis, and its disruption is embryonic lethal. beta4GalT-5-deficient embryos showed developmental retardation from E7.5 and died by E10.5 as reported previously. LacCer synthase activity was significantly reduced in beta4GalT-5-deficient embryos and extra-embryonic endoderm (XEN) cells derived from blastocysts, and it was recovered when beta4GalT-5 cDNA was introduced into beta4GalT-5-deficient XEN cells. The amounts of LacCer and GM3 ganglioside were drastically reduced, while GlcCer accumulated in the beta4GalT-5-deficient XEN cells. Hematoma and ectopically accumulated trophoblast giant cells were observed in the anti-mesometrial pole of the extra-embryonic tissues, although all three embryonic layers formed. beta4GalT-5-deficient embryos developed until E12.5 as chimeras with wild-type tetraploid cells, which formed the extra-embryonic membranes, indicating that extra-embryonic defects caused the early embryonic lethality. Our results suggest that beta4GalT-5 is essential for extra-embryonic development during early mouse embryogenesis.
authors.affiliation: Division of Transgenic Animal Science, Advanced Science Research Center, Kanazawa University, Kanazawa, Japan.
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Nishie
authors.forename: Yoko
authors.initials: Y
authors.lastname: Hikimochi
authors.forename: Kota
authors.initials: K
authors.lastname: Zama
authors.forename: Yoshiyasu
authors.initials: Y
authors.lastname: Fukusumi
authors.forename: Mitutoshi
authors.initials: M
authors.lastname: Ito
authors.forename: Haruka
authors.initials: H
authors.lastname: Yokoyama
authors.forename: Chie
authors.initials: C
authors.lastname: Naruse
authors.forename: Makoto
authors.initials: M
authors.lastname: Ito
authors.forename: Masahide
authors.initials: M
authors.lastname: Asano
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001755:Blastocyst / Q000378:metabolism; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology* / Q000378:metabolism; D047108:Embryonic Development; D004707:Endoderm / Q000502:physiology*; D005321:Extraembryonic Membranes / Q000378:metabolism*; D005260:Female; D005679:G(M3) Ganglioside / Q000378:metabolism; D005700:Galactosyltransferases / Q000378:metabolism* / Q000502:physiology*; D005804:Genes, Lethal; D015726:Giant Cells / Q000378:metabolism / Q000473:pathology; D006028:Glycosphingolipids; D006406:Hematoma / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D017403:In Situ Hybridization; D007790:Lactosylceramides / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008822:Mice, Transgenic; D057891:Tetraploidy; D014327:Trophoblasts / Q000378:metabolism / Q000473:pathology
chemical_list: D015703:Antigens, CD; D005679:G(M3) Ganglioside; D006028:Glycosphingolipids; D007790:Lactosylceramides; C009744:CDw17 antigen; D005700:Galactosyltransferases; C039090:UDPgalactose-glucosylceramide galactosyltransferase; C419408:beta-1,4-galactosyltransferase V