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Syntaxin 4 Expression Affects Glucose Transporter 8 Translocation and Embryo Survival

Department of Obstetrics and Gynecology (A.H.W., M.C., J.R., M.O.C., K.H.M.) and Department of Cell Biology and Physiology (K.H.M.),Washington University School of Medicine, St. Louis, Missouri 63110; Lexicon Genetics, Inc. (C.Y., K.J.C.), The Woodlands, Texas 77381; and The University of Iowa (J.E.P.), Iowa City, Iowa 52242

Address all correspondence and requests for reprints to: Kelle H. Moley, 4911 Barnes-Jewish Hospital Plaza, 6th Floor Maternity, St. Louis, Missouri 63110. E-mail: moleyk{at}msnotes.wustl.edu.

Target-soluble N-ethylmaleimide-sensitive factor attachment protein receptors (t-SNAREs) are receptors that facilitate vesicle and target membrane fusion. Syntaxin 4 is the t-SNARE critical for insulin-stimulated glucose transporter 4 (GLUT4)-plasma membrane fusion in adipocytes. GLUT8 is a novel IGF-I/insulin-regulated glucose transporter expressed in the mouse blastocyst. Similar to GLUT4, GLUT8 translocates to the plasma membrane to increase glucose uptake at a stage in development when glucose serves as the main substrate. Any decrease in GLUT8 cell surface expression results in increased apoptosis and pregnancy loss. Previous studies have also shown that disruption of the syntaxin 4 (Stx4a) gene results in early embryonic lethality before embryonic d 7.5. We have now demonstrated that syntaxin 4 protein is localized predominantly to the apical plasma membrane of the murine blastocyst. Stx4a inheritance, as detected by protein expression, occurs with the expected Mendelian frequency up to embryonic d 4.5. In parallel, 22% of the blastocysts from Stx4a+/- matings had no significant insulin-stimulated translocation of GLUT8 whereas 77% displayed either partial or complete translocation to the apical plasma membrane. This difference in GLUT8 translocation directly correlated with one-third of blastocysts from Stx4a+/- mating having reduced rates of insulin-stimulated glucose uptake and 67% with wild-type rates. These data demonstrate that the lack of syntaxin 4 expression results in abnormal movement of GLUT8 in response to insulin, decreased insulin-stimulated glucose uptake, and increased apoptosis. Thus, syntaxin 4 functions as the necessary t-SNARE protein responsible for correct fusion of the GLUT8-containing vesicle with the plasma membrane in the mouse blastocyst.

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