Foxa2 Is Essential for Mouse Endometrial Gland Development and Fertility1

Abstract

During embryonic development, Foxa2 is required for the formation of the node and notochord, and ablation of this gene results in defects in gastrulation, neural tube patterning, and gut morphogenesis. Foxa2 has been shown to be expressed specifically in the glandular epithelium of the murine uterus. To study the uterine function of Foxa2, this gene was conditionally ablated in the mouse uterus by crossing mice with floxed Foxa2 alleles, Foxa2(loxP/loxP), with the Pgr(cre) mouse model. Pgr(cre/+) Foxa2(loxP/loxP) mice showed significantly reduced fertility. Analysis of the uterus on Day 5.5 of pregnancy showed disrupted blastocyst implantation. Pgr(cre/+) Foxa2(loxP/loxP) mice also showed a severe impairment of the uterus to respond to the artificial induction of the decidual response. Morphological examination of the uteri of these mice showed a severe reduction in the number of endometrial glands. The loss of endometrial glands resulted in the reduction of leukemia inhibitory factor (Lif) expression. The lack of a decidual response could be partially rescued by an intrauterine injection of LIF before the initiation of the decidual response. This analysis demonstrates that Foxa2 regulates endometrial gland development and that mice with a loss of endometrial glands cannot support implantation in part due to the loss of LIF, which is a requisite for fertility in the mouse.

Physiological and molecular determinants of embryo implantation

“…Forkhead box A2 (Foxa2) is expressed specifically in the uterine glandular epithelium (Besnard et al, 2004). Uterine-specific ablation of this gene in mice results in defective uterine gland formation and dysfunctional uterine stroma unable to support embryo invasion and decidualization (Bazer, 2010; Jeong et al, 2010). Notably, LIF expression is significantly decreased in Foxa2 deficient uteri, whereas administration of recombinant LIF can partially restore decidualization in null females (Bazer, 2010; Jeong et al, 2010), suggesting that Foxa2 may be required for normal glandular LIF expression.…”

“…Uterine-specific ablation of this gene in mice results in defective uterine gland formation and dysfunctional uterine stroma unable to support embryo invasion and decidualization (Bazer, 2010; Jeong et al, 2010). Notably, LIF expression is significantly decreased in Foxa2 deficient uteri, whereas administration of recombinant LIF can partially restore decidualization in null females (Bazer, 2010; Jeong et al, 2010), suggesting that Foxa2 may be required for normal glandular LIF expression. Mice systemically lacking Wnt7a have a stratified luminal epithelium surrounded by a shallow stroma layer devoid of glands, in contrast to the simple columnar structure in the wild-type (Miller and Sassoon, 1998).…”

Uterine glands: biological roles in conceptus implantation, uterine receptivity and decidualization

“…Subsequently, LIF was found to be essential for blastocyst implantation in mice, as Lif null mice were infertile due to a failure of blastocyst implantation (Stewart et al ., 1992). Recent studies found that a number of knockout ( lymphoid enhancer factor 1 or Lef1 ) and conditional knockout mice [catenin (cadherin associated protein), beta 1 or Ctnnb1; forkhead box A2 or Foxa2, wingless-related MMTV integration site 4 or Wnt4; and Wnt7a ] lack glands in the adult uterus (Dunlap et al ., 2011, Franco et al ., 2011, Franco et al ., 2010, Jeong et al ., 2010, Jeong et al ., 2009, Shelton et al ., 2012). Many of those mice exhibit defects in blastocyst implantation and uterine decidualization and thus fertility, which can be attributed to the absence of LIF and other uterine gland-derived factors.…”

“…Results with the aglandular PUGKO mouse model, along with those from conditional Foxa2 mutant mice that have much reduced uterine glands (Jeong et al ., 2010) and Lif null mice (Stewart et al ., 1992), strongly support that hypothesis.…”

“…However, intrauterine LIF failed to rescue decidualization in ovariectomized PUGKO mice that lack uterine glands (Filant and Spencer, 2013b). Similarly, mice that have a conditional ablation of Foxa2 have a uterus with much reduced numbers of glands and exhibit severe defects in blastocyst implantation as well as stromal cell decidualization using an artificial model (Jeong et al ., 2010). Similarly, the uterus of conditional Wnt4 ablated mice also lack uterine glands and have a severely impaired artificial decidual response (Franco et al ., 2011).…”