Nutrient sensing by the early mouse embryo: hexosamine biosynthesis and glucose signaling during preimplantation development.
Although mouse oocytes and cleavage-stage embryos are unable to utilize glucose as a metabolic fuel, they have a specific requirement for a short exposure to glucose prior to compaction. The reason for this requirement has been unclear. In this study we confirm that cleavage-stage exposure to glucose is required for blastocyst formation and show that the absence of glucose between 18-64 h after hCG causes an irreversible decrease in cellular proliferation and an increase in apoptosis. More importantly, this glucose signals to activate expression of Slc2a3 transcript and SLC2A3 protein, a facilitative glucose transporter (previously known as GLUT3) associated with developmental competence and increased glucose uptake used to fuel blastocyst formation. Glucosamine could substitute for glucose in these roles, suggesting that hexosamine biosynthesis may be a nutrient-sensing mechanism involved in metabolic differentiation. Inhibition of the rate-limiting enzyme in this pathway, glutamine-fructose-6-phosphate amidotransferase (GFPT), inhibited expression of the SLC2A3 transporter protein and blastocyst formation. Glucosamine, a substrate that enters this pathway downstream of GFPT, was able to overcome this inhibition and support SLC2A3 expression. These data suggest that early embryos rely on hexosamine biosynthesis as a glucose-sensing pathway to initiate metabolic differentiation.
Pantaleon
Marie
M
School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, 4072 Australia. m.pantaleon@uq.edu.au
Scott
Jeanie
J
Kaye
Peter L
PL
D000818:Animals; D017209:Apoptosis; D001377:Azaserine / Q000494:pharmacology; D001755:Blastocyst / Q000502:physiology; D047108:Embryonic Development / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D005944:Glucosamine / Q000008:administration & dosage; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism*; D051274:Glucose Transporter Type 3 / Q000235:genetics; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) / Q000037:antagonists & inhibitors; D006595:Hexosamines / Q000096:biosynthesis*; D051379:Mice; D015398:Signal Transduction
D004791:Enzyme Inhibitors; D051274:Glucose Transporter Type 3; D006595:Hexosamines; C495689:Slc2a3 protein, mouse; D001377:Azaserine; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing); D005947:Glucose; D005944:Glucosamine