Abstract
The STAT3 transcription factor is a pleiotropic transducer of signalling by hormones, growth factors and cytokines that has been identified in the female reproductive tract from oocytes and granulosa cells of the ovary to uterine epithelial and stromal cells. In the present study we used transgenic models to investigate the importance of STAT3 for reproductive performance in these different tissues. The Cre-LoxP system was used to delete STAT3 in oocytes by crossing Stat3fl/fl with Zp3-cre+ mice, or in ovarian granulosa cells and uterine stroma by crossing with Amhr2-Cre+ mice. Surprisingly, deletion of STAT3 in oocytes had no effect on fertility indicating that the abundance of STAT3 protein in maturing oocytes and fertilized zygotes is not essential to these developmental stages. In Stat3fl/fl;Amhr2-cre+ females impaired fertility was observed through significantly fewer litters and smaller litter size. Ovulation rate, oocyte fertilization and development to blastocyst were unaffected in this line; however, poor recombination efficiency in granulosa cells had yielded no net change in STAT3 protein abundance. In contrast, uteri from these mice showed STAT3 protein depletion selectively from the stomal compartment. A significant reduction in number of viable fetuses on gestational day 18, increased fetal resorptions and disrupted placental morphology were evident causes of the reduced fertility. In conclusion, this study defines an important role for STAT3 in uterine stromal cells during embryo implantation and the development of a functional placenta.
Highlights
Female reproductive organ function is controlled and coordinated by an intricate network of signalling hormones, growth factors and cytokines [1,2]
Fertility was compared in the oocyte mutant Stat3fl/fl; Zp3-cre+ females and control genotypes by evaluating production of offspring in breeding pairs over a 26 week period
signal transducer and activator of transcription 3 (STAT3) is expressed in multiple female reproductive tissues where it potentially transduces signals from many cytokines and growth factors that influence reproductive processes
Summary
Female reproductive organ function is controlled and coordinated by an intricate network of signalling hormones, growth factors and cytokines [1,2]. STAT3 protein is tyrosine phosphorylated by the Janus kinases (JAK) and by receptor tyrosine kinases in response to cytokine and growth factor signals. Growth and atresia are major biological checkpoints that control female reproductive potential and establish the developmental potential of the resultant embryo [4]. Growth factors and cytokines all contribute to the control of follicle activation and development [2,5]. Cytokines that signal via STAT3 are thought to act on oocytes [9], suggesting that STAT3 may be a key mediator of regulated gene transcription in the oocyte
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