TY - JOUR
T1 - β4-Galactosyltransferase-5 is a lactosylceramide synthase essential for mouse extra-embryonic development
AU - Nishie, Toshikazu
AU - Hikimochi, Yoko
AU - Zama, Kota
AU - Fukusumi, Yoshiyasu
AU - Ito, Mitutoshi
AU - Yokoyama, Haruka
AU - Naruse, Chie
AU - Ito, Makoto
AU - Asano, Masahide
N1 - Funding Information:
This work was supported in part by Grant-in-Aid for Scientific Research (B) (grant No. 19300144) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
PY - 2010/10
Y1 - 2010/10
N2 - 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 β4-galactosyltransferase-6 (β4GalT-6) gene in the rat brain. However, the existence of another LacCer synthase gene was shown in cultured cells lacking β4GalT-6. Here, we report that LacCer synthase is mainly synthesized by the β4GalT-5 gene during early mouse embryogenesis, and its disruption is embryonic lethal. β4GalT-5-deficient embryos showed developmental retardation from E7.5 and died by E10.5 as reported previously. LacCer synthase activity was significantly reduced in β4GalT-5-deficient embryos and extra-embryonic endoderm (XEN) cells derived from blastocysts, and it was recovered when β4GalT-5 cDNA was introduced into β4GalT-5-deficient XEN cells. The amounts of LacCer and GM3 ganglioside were drastically reduced, while GlcCer accumulated in the β4GalT-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. β4GalT-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 β4GalT-5 is essential for extra-embryonic development during early mouse embryogenesis.
AB - 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 β4-galactosyltransferase-6 (β4GalT-6) gene in the rat brain. However, the existence of another LacCer synthase gene was shown in cultured cells lacking β4GalT-6. Here, we report that LacCer synthase is mainly synthesized by the β4GalT-5 gene during early mouse embryogenesis, and its disruption is embryonic lethal. β4GalT-5-deficient embryos showed developmental retardation from E7.5 and died by E10.5 as reported previously. LacCer synthase activity was significantly reduced in β4GalT-5-deficient embryos and extra-embryonic endoderm (XEN) cells derived from blastocysts, and it was recovered when β4GalT-5 cDNA was introduced into β4GalT-5-deficient XEN cells. The amounts of LacCer and GM3 ganglioside were drastically reduced, while GlcCer accumulated in the β4GalT-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. β4GalT-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 β4GalT-5 is essential for extra-embryonic development during early mouse embryogenesis.
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U2 - 10.1093/glycob/cwq098
DO - 10.1093/glycob/cwq098
M3 - Article
C2 - 20574042
AN - SCOPUS:77956520108
VL - 20
SP - 1311
EP - 1322
JO - Glycobiology
JF - Glycobiology
SN - 0959-6658
IS - 10
ER -