Abstract
The phosphatidylinositol 3-kinase (PI3K) signal transduction pathway is a well known mediator of cell growth, proliferation, and survival signals. Whereas the expression and function of this pathway has been documented during mammalian development, evidence demonstrating the physiologic importance of this pathway in murine preimplantation embryos is beginning to emerge. This study demonstrates that inhibition of the PI3K pathway leads to the induction of apoptosis in both murine blastocysts and trophoblast stem cells. The apoptosis induced in both model systems correlates with a decrease in the expression of the glucose transporter GLUT1 at the plasma membrane. In addition, blastocysts cultured in the presence of the PI3K inhibitor LY-294002 display a decrease in both 2-deoxyglucose uptake and hexokinase activity as compared with control blastocysts. To determine the impact of PI3K inhibition on pregnancy outcome, embryo transfer experiments were performed. Blastocysts cultured in the presence of LY-294002 demonstrate a dramatic increase in fetal resorptions as compared with control embryos. Finally, we demonstrate that impairment of glucose metabolism via iodoacetate, a glyceraldehyde-3-phosphate dehydrogenase inhibitor, is sufficient to induce apoptosis in both blastocysts and trophoblast stem cells. Moreover, blastocysts treated with iodoacetate result in poor pregnancy outcome as determined by embryo transfer experiments. Taken together these data demonstrate the critical importance of the PI3K pathway in preimplantation embryo survival and pregnancy outcome and further emphasize the importance of glucose utilization and metabolism in cell survival pathways.
Highlights
Known to activate the phosphatidylinositol 3-kinase (PI3K)2 pathway including the insulin and insulin-like growth factor-I receptors [3, 4]
We and others demonstrated that the PI3K pathway is present and functional during murine preimplantation development [32, 34, 35, 42]; there is still relatively little data regarding the physiologic ramifications of inhibiting this pathway in preimplantation embryos
Because of the connection between the PI3K signal transduction pathway, growth factors, and cell survival in other systems [18, 43], we first investigated whether inhibition of PI3K results in the induction of apoptosis
Summary
Known to activate the phosphatidylinositol 3-kinase (PI3K) pathway including the insulin and insulin-like growth factor-I receptors [3, 4]. The PI3K/Akt pathway has been examined during different developmental processes, relatively little is known about this pathway during the preimplantation period This is a critical stage during development as several studies have suggested that perturbations in glucose and amino acid metabolism may have long lasting effects on later development [27,28,29,30,31]. We demonstrated that the 85-kDa regulatory subunit and the 110-kDa catalytic subunit of PI3K as well as the serine-threonine kinase Akt are expressed from the 1-cell through the blastocyst stage of murine preimplantation embryo development [32]. These proteins are localized predominantly at the cell surface from the 1-cell through the morula stage. PI3K Regulates Glucose Metabolism and Embryo Survival preimplantation development implying that this pathway is being continuously activated by endogenous growth factors during this early developmental period
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