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J. Biol. Chem., Vol. 281, Issue 9, 6010-6019, March 3, 2006

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Phosphatidylinositol 3-Kinase Activity Is Critical for Glucose Metabolism and Embryo Survival in Murine Blastocysts^*

Joan K. Riley, Mary O. Carayannopoulos, Amanda H. Wyman, Maggie Chi, and Kelle H. Moley^¶1

From the Departments of Obstetrics and Gynecology, ^¶Cell Biology and Physiology and Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110

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.

Received for publication, June 27, 2005 , and in revised form, October 27, 2005.

^* This work was supported by a Juvenile Diabetes Research Foundation Fellowship (to J. K. R.) and National Institutes of Health Grants HD40390 and DK0070351 (to K. H. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Box 8064, 4911 Barnes-Jewish Hospital Plaza, St. Louis, MO 63110. Tel.: 314-362-1997; Fax: 314-747-4150; E-mail: moleyk{at}wustl.edu.

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