Abstract
Foxa2 is a member of the winged helix/forkhead box (Fox) transcription factor family is expressed in the glandular epithelium of the murine uterus. 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. The function of Foxa2 in the adult mouse uterus was investigated by the conditional ablation of Foxa2. This was accomplished by crossing mice with floxed Foxa2 alleles, Foxa2loxP/loxP, with the PRCre mouse model. The PRcre mouse ablates loxP-flanked genes in the pituitary, corpus luteum of the ovary, uterus and mammary gland. Foxa2loxP/loxP; PRCre (or Foxa2d/d for short) mice showed significantly reduced fertility and sterility with increasing age. Morphological examination of the uteri of these mice showed a severe reduction in the number of endometrial glands. Functional analysis of the uterus was investigating by the artificial induction of the uterine decidual response. This was accomplished by treating ovariectomized mice with progesterone and estrogen and initiating the decidual reaction with a scratch trauma. Decidualization was assayed by measuring an increase in uterine weight and expression of alkaline phosphatase in the endometrial stroma cells. The Foxa2d/d mice showed a severe inhibition of the decidual response when compared to Foxa2loxP/loxP control mice. This lack of decidual response could be rescued by intrauterine injection of 10 μl of Leukemia Inhibitory factor (100ng/μl), LIF, prior to the initiation of the decidual response. This analysis demonstrates that Foxa2 regulates endometrial gland development. Mice with loss of endometrial glands cannot support implantation most likely due to the loss of LIF which is a requisite for fertility in the mouse. This work was supported by NICHD/NIH as part of the Cooperative Program on Trophoblast-Maternal Tissue Interactions (U01 HD042311) and the Specialized Cooperative Center for Reproductive Research (U54 DK59820). (platform)
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