Implantation of the mammalian embryo into the wall of the uterus is regulated by a timely interplay of the ovarian hormones, estrogen and progesterone. These hormones orchestrate a set of modifications in the uterine endometrium that transforms it from a nonreceptive to a receptive phase allowing the implantation of the developing blastocyst. The molecular and cellular mechanisms underlying this complex process, however, remain largely unknown. To investigate the endocrine basis of uterine receptivity, we employed a gene expression screen technique to identify factors whose expressions are modulated in the rat uterus in response to estrogen and progesterone at the onset of implantation. Here we report that the expression of calcitonin, a peptide hormone involved in calcium homeostasis, is markedly enhanced in the uterus during pregnancy. By Northern blot analysis, we show that the synthesis of calcitonin messenger RNA is induced at the time of implantation. Immunocytochemistry with calcitonin antibody demonstrates further that the peptide is localized in the glandular epithelial cells of the uterus. The antiprogestin drug RU486, which is known to block implantation, abolishes calcitonin expression, suggesting a regulatory role for progesterone in this process. Consistent with this observation, progesterone significantly stimulates calcitonin messenger RNA and protein synthesis in the uteri of ovariectomized animals. Our study, therefore, identifies calcitonin as a stage- and cell-specific marker of progesterone action in the uterus during pregnancy. Estrogen exhibits no significant effect on calcitonin expression when administered alone to ovariectomized animals. However, a low dose of estrogen synergizes with progesterone, and a high dose antagonizes progesterone-mediated gene induction. Both estrogen and progesterone, therefore, modulate calcitonin gene expression in the uterus. The stage-specific regulation of calcitonin is apparently determined by the relative concentrations and the sequences of appearance of these two hormones and possibly other as yet unknown regulatory factors during pregnancy. We propose that calcitonin, a known regulator of calcium levels in the bone and kidney, may play an important regulatory role in the uterus of pregnant animals during the early events leading to implantation of the embryo.
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