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Submitted on March 16, 2004
Accepted on May 25, 2004
Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, United Kingdom.; Department of Obstetrics and Gynaecology, University of Cambridge, The Rosie Hospital, Cambridge, CB2 2SW, United Kingdom.; Microarray Development Group, UK HGMP Resource Centre, Hinxton Hall, Cambridge, CB10 1SB, United Kingdom.; School of Biological Sciences, University of Manchester, M13 9PT, United Kingdom.; Centre for Genome Research, University of Edinburgh, Edinburgh, EH9 3QJ, United Kingdom
* To whom correspondence should be addressed. E-mail: jras100{at}cam.ac.uk.
The endometrium is prepared for implantation by the actions of estradiol and progesterone. In mice the luminal epithelium only becomes fully receptive to the attaching blastocyst in response to the nidatory estrogen surge on day 4 of pregnancy. The cytokine leukemia inhibitory factor (LIF) is rapidly induced by nidatory estrogen and has been shown to be the primary mediator of its action. Implantation fails in the absence of LIF and injection of LIF on day 4 of pregnancy can substitute for the nidatory estrogen. In this study, we sought to identify genes regulated by LIF in the uterine epithelium. We used oligonucleotide microarrays to compare the transcript profiles of paired uterine horns from LIF deficient MF1 mice after intraluminal injection of LIF or PBS on day 4 of pseudopregnancy. Insulin-like growth factor binding protein 3 (IGFBP3) was identified as a gene upregulated by LIF; this was confirmed by RT-PCR. In situ hybridization showed that the primary site of IGFBP3 expression is the luminal epithelium, the known site of LIF action in the uterus. We identified two other genes: amphiregulin and immune response gene-1 (IRG1) whose expression was also upregulated by LIF. IRG1 has recently been shown to be essential for implantation. Expression of all three of these genes in the luminal epithelium is known to be regulated by progesterone. The expression of OSF-2 and L-12/15 Lox, which are also expressed in luminal epithelium under the control of progesterone, were not increased by LIF. This suggests that one of the actions of LIF on luminal epithelium may be to enhance the expression of a subset of progesterone regulated genes.
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