Evidence for a conserved function of heart and neural crest derivatives expressed transcript 2 in mouse and human decidualization.

Previously, we showed that heart and neural crest derivatives expressed transcript 2 (Hand2) mRNA levels dramatically increase in mouse uterine endometrial stromal cells (ESCs) as they undergo decidualization in vivo. However, to date, little is known about the expression and function of this transcription factor in mouse or human uterus decidualization. Therefore, this study was conducted to provide a more detailed assessment of Hand2 gene expression and function in the mouse uterus during the peri-implantation period and also in mouse plus human ESCs during decidualization in vitro. The results show that Hand2 mRNA and protein levels increase in the mouse uterus during decidualization and this does not depend on the presence of a conceptus. Interestingly, Hand2 mRNA and protein are present in ESCs adjacent to the luminal epithelium in the uterus prior to the onset of implantation. We find that progesterone is likely a regulator of Hand2 expression during uterine sensitization of the mouse uterus. Finally, Hand2 expression increases in mouse and human fibroblast cells as they undergo decidualization in vitro. This expression is significantly increased in response to prostaglandin E(2). In particular, reduction of Hand2 expression in these cells using small hairpin RNA or small interfering RNA approaches results in the reduced extent of decidualization as shown by the reduced expression of a subset of decidualization markers. The results of this study support the hypothesis that Hand2 expression not only plays an important role in decidualization but may also play a role in obtaining proper progesterone-dependent uterine sensitization required for implantation to begin.