LIF AND PRL AND UTERINE PREPARATION FOR NIDATION

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The long term objectives of this research are to elucidate the physiological mechanisms controlling obligate delay of implantation and embryonic diapause in a carnivore that exhibits an obligate delay of implantation lasting 200 +/- 20 days. The overall thesis is that changes in the uterine environment are ultimately responsible for resumption of embryonic development. The uterine epithelium of the mouse secretes leukemia inhibitory factor (LIF). Deletion of the gene for LIF prevents implantation and results in embryonic diapause in mice. Administration of LIF to pregnant LIF- females induces renewed embryonic development and implantation. Nothing is known about the role of LIF in the regulation of implantation in any other species; however, human uterine LIF mRNA concentrations are highest at the predicted time of implantation. The proposed research will test the hypothesis that LIF plays a role in inducing resumption of embryonic development and implantation in a species that exhibits obligate delay of implantation. The first two experiments will determine whether uterine LIF mRNA concentrations increase at the time of implantation and whether prolactin (PRL) or ovarian steroids will enhance uterine LIF mRNA concentrations. The next experiment will determine whether 125I-rhLIF will bind to the uterus or blastocysts. We will then determine whether constant administration of LIF will induce implantation in females with dormant blastocysts as it does in the mouse. Our previous studies have demonstrated that PRL plays a pivotal role in regulating implantation in mustelid carnivores. Constant administration of PRL hastens implantation and stimulates ovarian activity as indicated by increased progesterone secretion. The uterus of mustelid carnivores also possess PRL binding sites. A second series of experiments will test the hypothesis that PRL has a role in preparing the uterus for implantation. First we will determine the location of PRLr in the uterus and whether uterine PRLr mRNA concentrations increase at the time of implantation. We will then attempt to determine whether PRL might alter the uterine environment by: l) enhancing uterine concentration of progesterone receptors, 2) increasing uterine binding of LIF, or 3) promoting development of endometrial glands.