Forkhead box a2 (FOXA2) is essential for uterine function and fertility

Andrew M Kelleher; Wang Peng; James K Pru; Cindy A Pru; Francesco J DeMayo; Thomas E Spencer

doi:10.1073/pnas.1618433114

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Forkhead box a2 (FOXA2) is essential for uterine function and fertility

Journal article

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Forkhead box a2 (FOXA2) is essential for uterine function and fertility

Andrew M Kelleher, Wang Peng, James K Pru, Cindy A Pru, Francesco J DeMayo and Thomas E Spencer

Proceedings of the National Academy of Sciences - PNAS, Vol.114(6), pp.E1018-E1026

02/07/2017

DOI: https://doi.org/10.1073/pnas.1618433114

Handle:

https://hdl.handle.net/2376/105017

PMCID: PMC5307455

PMID: 28049832

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https://doi.org/10.1073/pnas.1618433114View

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Abstract

Animals, Newborn

Hepatocyte Nuclear Factor 3-beta - metabolism

Hepatocyte Nuclear Factor 3-beta - genetics

Humans

Uterus - metabolism

Embryo Implantation - genetics

Gene Expression Regulation

Male

Mice, Transgenic

Leukemia Inhibitory Factor - genetics

Decidua - metabolism

Infertility - genetics

Leukemia Inhibitory Factor - metabolism

Mice, Knockout

Fertility - genetics

Animals

Female

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.

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Title: Forkhead box a2 (FOXA2) is essential for uterine function and fertility
Creators: Andrew M Kelleher - Division of Animal Sciences, University of Missouri, Columbia, MO 65211
Wang Peng - Division of Animal Sciences, University of Missouri, Columbia, MO 65211
James K Pru - Department of Animal Sciences, Washington State University, Pullman, WA 99164
Cindy A Pru - Department of Animal Sciences, Washington State University, Pullman, WA 99164
Francesco J DeMayo - Pregnancy and Female Reproduction Group, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709
Thomas E Spencer - Division of Animal Sciences, University of Missouri, Columbia, MO 65211; spencerte@missouri.edu
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.114(6), pp.E1018-E1026
Academic Unit: Animal Sciences, Department of
Publisher: United States
Grant note: R21 HD076347 / NICHD NIH HHS
Identifiers: 99900546994101842
Language: English
Resource Type: Journal article