Signal transducers and activators of transcription-3 (STAT3) is a transcription factor activated by JAK kinases after cytokine-receptor binding. We have identified active phospho-STAT3 in granulosa cells of ovarian follicles from the very early activated stage. Abundant STAT3 has also been identified by us and others in oocytes, cumulus and granulosa cells of mature preovulatory follicles. Further, we have found the STAT responsive gene product SOCS4 is present in granulosa cells of early activated and growing follicles (1). To determine the role of STAT3 in follicle growth and ovulation we have generated three unique lines of conditional STAT3 null mice with STAT3 deletion in granulosa cells or oocytes. Mice with STAT3 gene sequenced flanked by LoxP elements (STAT3^fl/fl) were crossed with lines expressing Cre-recombinase in granulosa cells (AmhR2-Cre, FSHR-Cre) or oocytes (ZP3-Cre). Fertility analysis of STAT3^fl/fl;Zp3-Cre females crossed with wildtype males showed no effect on fertility from STAT3 deletion in the oocyte. In contrast, both FSHR-Cre and AmhR2-Cre mediated granulosa deficient STAT3 lines had significantly reduced litter sizes; 1.4-fold and 1.9-fold lower respectively compared to control littermates (STAT3^fl/+;Cre⁺ or STAT3^fl/fl;Cre-). Furthermore AmhR2-Cre mediated STAT3 deletion resulted in a significant 1.9-fold reduction in litters per month and an increased time to first litter. Surprisingly we did not find any difference in ovulation rate after eCG+hCG stimulated superovulation, nor in naturally cylcing mice. Zygotes flushed the morning after mating and placed into culture showed no deficit in cleavage of 2-cell embryos or development to blastocyst. A potential uterine deficiency was investigated and gross morphological observations indicate a defect in the uteri which is consistent with the recent report of Cre-recombinase expression in uterine cells derived from the Mullerian duct mesenchyme (2). Thus STAT3 deficiency in oocytes does not lead to infertility while AmhR2-Cre and FSHR-Cre mediated STAT3 deficiency leads to a sub-fertile phenotype.

(1) Keightley RA, et al. 2009 Reprod, Fertil Dev 21(Suppl.): 509.
(2) Gonzalez G, Behringer RR. 2009 Mol Reprod Dev 76: 678–688.