Hunting for Fox(A2): Dual roles in female fertility

Abstract

Pregnancy encompasses a complex orchestration of several sequential steps across tissue and cell types in the mother and fetus for embryo development and delivery of offspring at an opportune time for survival. These steps include embryo implantation, stromal cell proliferation and differentiation (decidualization), placentation, and ultimately parturition with delivery of offspring (1, 2). The outcome of each stage depends on the success of the preceding stages. Most pregnancy events in mice and other mammals are primarily regulated by ovarian estrogen and progesterone (2), yet the molecular discourse between the reproductive system and the embryo that guides pregnancy events is a prevailing mystery. The uterus is primarily comprised of two compartments: the outermost muscle layer (myometrium) and the underlying endometrium. The endometrium is composed of the stroma, the epithelium, and glands. These glands have been seen throughout pregnancy and are acknowledged as essential for implantation and pregnancy success (3), yet their formation and particular genetic and molecular contributions during distinct stages of pregnancy have not been fully appreciated. In PNAS, Kelleher et al. (4) show that Forkhead box a2 (FOXA2), a transcription factor expressed in neonatal and adult mouse uteri, plays dual, stage-specific roles in maternal tissues during pregnancy (Fig. 1).The development of glands (adenogenesis) begins in the postnatal uterus, and their maturation and differentiation is under endocrine control during adulthood. Gland formation and secretions during pregnancy are essential for successful reproduction in mammals. Uterine gland knockout ewes do not form glands, nor do they cycle. These ewes are infertile (3, 5), suggesting that uterine glands are required for conceptus survival and development. Adenogenesis is associated with several signaling pathways and their development and maturation has been linked with growth factors, Wnt signaling, and homeobox signaling pathways (6, 7).FoxA2 is a homeobox transcription factor required during embryogenesis and plays multiple critical roles in gastrulation, neural tube patterning, and gastrointestinal development (8, 9). FoxA2 is also expressed in glands in the pregnant mouse uterus, suggesting its role in pregnancy (10). Because systemic deletion of FoxA2 results in embryonic lethality, its role was evaluated during pregnancy by transgenic mice with FoxA2 conditionally ablated in the mouse uterus (10, 11). These mice had significantly reduced fertility with smaller litter sizes as a result of disrupted embryo implantation. Blastocysts in mutant females could attach to the uterine luminal epithelium (LE) with appropriate expression of uterine receptivity marker genes. However, the embryo could not penetrate the LE for implantation or initiate stromal cell decidual responses in most of the females studied. The number of endometrial glands was severely reduced in FoxA2 mutant mice, precluding the secretion of leukemia inhibitory factor (Lif) expression, a critical fac...

Uterine glands coordinate on-time embryo implantation and impact endometrial decidualization for pregnancy success

“…In glandless mice ( Pgr Cre/ + Foxa2 f/f ), pregnancies fail by GD 10, whereas they are maintained to term in gland-containing FOXA2-deficient mice ( Ltf iCre/ + Foxa2 f/f ). These studies strongly support the hypothesis that uterine glands and, by inference, their products have essential biological roles in embryo implantation and stromal cell decidualization for the establishment of pregnancy 18 .…”

Efficient cell chatting between embryo and uterus ensures embryo implantation

“…FoxA2 is a pivotal factor for implantation by regulating LIF expression in glands [ 31 , 32 ]. As a multiple face factor, the function of FoxA2 is overtly different in neonatal and adult mice [ 33 , 34 ]. The FoxA family members interact with ERα to influence epigenetic signature establishment in the presence of E2 in MCF7 cells [ 35 ].…”