title: Forkhead box a2 (FOXA2) is essential for uterine function and fertility.
abstract: Establishment of pregnancy is a critical event, and failure of embryo implantation and stromal decidualization in the uterus contribute to significant numbers of pregnancy losses in women. Glands of the uterus are essential for establishment of pregnancy in mice and likely in humans. Forkhead box a2 (FOXA2) is a transcription factor expressed specifically in the glands of the uterus and is a critical regulator of postnatal uterine gland differentiation in mice. In this study, we conditionally deleted FOXA2 in the adult mouse uterus using the lactotransferrin Cre (Ltf-Cre) model and in the neonatal mouse uterus using the progesterone receptor Cre (Pgr-Cre) model. The uteri of adult FOXA2-deleted mice were morphologically normal and contained glands, whereas the uteri of neonatal FOXA2-deleted mice were completely aglandular. Notably, adult FOXA2-deleted mice are completely infertile because of defects in blastocyst implantation and stromal cell decidualization. Leukemia inhibitory factor (LIF), a critical implantation factor of uterine gland origin, was not expressed during early pregnancy in adult FOXA2-deleted mice. Intriguingly, i.p. injections of LIF initiated blastocyst implantation in the uteri of both gland-containing and glandless adult FOXA2-deleted mice. Although pregnancy was rescued by LIF and was maintained to term in uterine gland-containing adult FOXA2-deleted mice, pregnancy failed by day 10 in neonatal FOXA2-deleted mice lacking uterine glands. These studies reveal a previously unrecognized role for FOXA2 in regulation of adult uterine function and fertility and provide original evidence that uterine glands and, by inference, their secretions play important roles in blastocyst implantation and stromal cell decidualization.
authors.affiliation: Division of Animal Sciences, University of Missouri, Columbia, MO 65211.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Kelleher
authors.affiliation: Division of Animal Sciences, University of Missouri, Columbia, MO 65211.
authors.forename: Wang
authors.initials: W
authors.lastname: Peng
authors.affiliation: Department of Animal Sciences, Washington State University, Pullman, WA 99164.
authors.forename: James K
authors.initials: JK
authors.lastname: Pru
authors.affiliation: Department of Animal Sciences, Washington State University, Pullman, WA 99164.
authors.forename: Cindy A
authors.initials: CA
authors.lastname: Pru
authors.affiliation: Pregnancy and Female Reproduction Group, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
authors.forename: Francesco J
authors.initials: FJ
authors.lastname: DeMayo
authors.affiliation: Division of Animal Sciences, University of Missouri, Columbia, MO 65211; spencerte@missouri.edu.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Spencer
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D003656:Decidua / Q000378:metabolism; D010064:Embryo Implantation / Q000235:genetics; D005260:Female; D005298:Fertility / Q000235:genetics*; D005786:Gene Expression Regulation; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007246:Infertility / Q000235:genetics*; D053605:Leukemia Inhibitory Factor / Q000235:genetics / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D008822:Mice, Transgenic; D014599:Uterus / Q000378:metabolism*
chemical_list: C496503:Foxa2 protein, mouse; D053605:Leukemia Inhibitory Factor; D051542:Hepatocyte Nuclear Factor 3-beta
keywords: FOXA2; LIF; gland; pregnancy; uterus