Editors' ChoiceReproductive Biology

A Helping Hand for Implantation

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Sci. Signal.  22 Feb 2011:
Vol. 4, Issue 161, pp. ec55
DOI: 10.1126/scisignal.4161ec55

Estrogen and progesterone cooperate to establish the proper uterine environment for embryo implantation. In mice, a preovulatory surge of estrogen promotes proliferation of the uterine epithelium during the 2 days after ovulation. Progesterone then inhibits this growth and stimulates differentiation of epithelial cells into the decidua, which will contribute to the placenta and is required for implantation of fertilized zygotes on the fourth day after ovulation. Li et al. identified the basic helix-loop-helix transcription factor Hand2, which was localized to the stroma underlying the uterine epithelium, as a potential target of regulation by the progesterone receptor (PR). Hand2 transcripts decreased in abundance in peri-implantation uteri of mice treated with the PR antagonist RU-486 and increased in uterine stromal cells in animals injected with progesterone after ovariectomy. Conditional knockouts in which uterine Hand2 was deleted (Hand2d/d) resulted in female infertility due to implantation failure. Although the abundance of estrogen, progesterone, and their receptors was normal in Hand2d/d animals, the postovulation rise of progesterone failed to down-regulate estrogen signaling, as determined by the abundance of activated estrogen receptor α (ERα) and the expression of estrogen-responsive genes in the uterine epithelium, and failed to activate transcription of progesterone-responsive genes in both the epithelium and stroma. Uterine epithelial cells ceased proliferating 4 days after ovulation in wild-type (WT) mice but continued dividing in Hand2d/d animals. Four genes encoding fibroblast growth factors (FGFs)—Fgf1, Fgf2, Fgf9, and Fgf18—showed increased expression in Hand2d/d uterine stroma, and FGF signaling through the extracellular signal–regulated kinases 1 and 2 (ERK1/2) increased in Hand2d/d uterine epithelia on postovulation day 4 relative to that in WT mice. Treatment with an FGF receptor inhibitor or ERK inhibitor decreased proliferation and ERα activation in Hand2d/d uterine epithelia. These results support a model in which FGFs produced by the uterine stroma stimulate proliferation of the overlying epithelium, and progesterone-induced Hand2 interrupts this mitogenic paracrine signaling to allow implantation.

Q. Li, A. Kannan, F. J. DeMayo, J. P. Lydon, P. S. Cooke, H. Yamagishi, D. Srivastava, M. K. Bagchi, I. C. Bagchi, The antiproliferative action of progesterone in uterine epithelium is mediated by Hand2. Science 331, 912–916 (2011). [Abstract] [Full Text]

S. C. Hewitt, K. S. Korach, A hand to support the implantation window. Science 331, 863–864 (2011). [Abstract] [Full Text]