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Cyclin G1 and Cyclin G2 Are Expressed in the Periimplantation Mouse Uterus in a Cell-Specific and Progesterone-Dependent Manner: Evidence for Aberrant Regulation with Hoxa-10 Deficiency

Division of Reproductive and Developmental Biology, Departments of Pediatrics (L.Y., T.D., X.H., M.L., H.W., S.K.De., S.K.Da.), Cancer Biology (X.H., M.L., S.K.Da.), Cell and Developmental Biology (L.Y., T.D., H.W., S.K.De.), and Pharmacology (L.Y., T.D., H.W., S.K.De.), Vanderbilt University Medical Center, Nashville, Tennessee 37232; and Department of Molecular Genetics (H.N.), Research Institute for Microbial Diseases, Osaka University, 565-0871 Osaka, Japan

Address all correspondence and requests for reprints to: Sanjoy K. Das, Division of Reproductive and Developmental Biology, Departments of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee 37232. E-mail: sanjoy.das{at}vanderbilt.edu.

Because uterine cell-specific proliferation, differentiation, and apoptosis are differentially regulated during the periimplantation period, we speculated that negative cell cycle regulators are also operative in the uterus during this period. This prompted us to examine the roles of two negative growth-regulatory genes, cyclin G1 and cyclin G2, in the periimplantation mouse uterus. We show that cyclin G1 and cyclin G2 genes are differentially regulated in the uterus during this period (d 1–8 of pregnancy) in a spatiotemporal manner. The results suggest that cyclin G1 is primarily associated with epithelial cell differentiation before implantation and stromal cell proliferation and differentiation during decidualization, whereas cyclin G2 is associated with terminal differentiation and apoptosis of the luminal epithelial and stromal cells at the site of blastocyst after implantation. Pharmacological and genetic studies provide evidence that the expression of cyclin G1, not cyclin G2, is regulated by progesterone via its nuclear receptor. Furthermore, the expression of these genes is aberrantly up-regulated in homeo box A-10 mutant uteri, suggesting that cyclin G1 and cyclin G2 genes act as downstream targets of homeobox A-10 and negatively impact uterine cell proliferation. Collectively, our present and previous studies suggest that negative cell cycle regulators collaborate with growth-promoting regulators in regulating uterine cell-specific proliferation, differentiation, and apoptosis relevant to implantation and decidualization.

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