Acute-phase response factor is a latent cytoplasmic transcription factor that is rapidly activated in response to interleukin-5 (IL5; 147850), interleukin-6 (IL6; 147620), epidermal growth factor (131530), leukemia inhibitory factor (159540), oncostatin M (165095), interleukin-11 (147681), and ciliary neurotrophic factor (118945).
General function
Intracellular signaling cascade, Nucleic acid binding, DNA binding, Transcription factor
Comment
Cellular localization
Cytoplasmic, Nuclear
Comment
Association of serum and follicular fluid leptin concentrations with granulosa cell phosphorylated signal transducer and activator of transcription 3 expression in fertile patients with polycystic ovarian syndrome. Li MG et al. (2007) Our objective was to evaluate whether polycystic ovarian syndrome (PCOS)-associated infertility is related to alterations of leptin, leptin receptor (Ob-R), and the phosphorylated signal transducer and activator of transcription 3 (p-STAT3)/suppressor of cytokine signal 3 (SOCS3) system in the ovary. A case-control study was conducted in a university hospital. Thirty-one infertile PCOS women with oligoovulation plus polycystic ovarian morphology and 79 infertile women with tubal blockage (control) participated in the study. The subjects were stratified according to in vitro fertilization outcomes: successful and failed subgroups. Serum and follicular fluid (FF) leptin levels were measured with ELISA. RT-PCR and Western blotting were performed to assess expression of mRNA encoding leptin and Ob-R and proteins of p-STAT3 and SOCS3 in granulosa cells (GCs). Leptin levels in serum and FF of PCOS women were significantly higher than those of control (P < 0.01). There were no significant differences in expression of leptin mRNA and short and long Ob-Rs between PCOS and control (P > 0.05). The p-STAT3 level was decreased in PCOS compared with control (P < 0.01), whereas SOCS3 remained significantly unchanged (P > 0.05). Further analysis showed that serum and FF leptin levels were significantly higher, whereas p-STAT3 in GCs was lower in the failed subgroup of PCOS than those in the successful subgroup of PCOS (P < 0.05). Hyperleptinemia and high FF leptin are important pathologies of PCOS with infertility. Lower levels of p-STAT3 in GCs may be related to ovarian leptin resistance and fecundity in PCOS women. Relatively high serum and FF leptin and low p-STAT3 in GCs may account for decreased fertilization, implantation, and pregnancy rates of in vitro fertilization in PCOS women.//////////////////
Ovarian function
Ovulation, Oogenesis, Oocyte maturation
Comment
Dynamic Changes in pStat3 are Involved in Meiotic Spindle Assembly in Mouse Oocytes. Haraguchi S et al. (2020) The signal transducer and activator of transcription 3 (Stat3) is activated upon phosphorylation at Y705 (pStat3) and serves the dual function of signal transduction and transcription activation. Our previous study suggested that pStat3 is functional during oocyte maturation when transcription is silenced. Therefore, we speculated that pStat3 serves other functions. Immunocytochemical analysis revealed that pStat3 emerges at microtubule asters and spindle and is subsequently localized at the spindle poles along with pericentrin during mouse oocyte maturation. Both Stat3 and pStat3 proteins were detected in conditionally knocked out Stat3-/- mouse oocytes. pStat3 localization was the same in Stat3+/+ and Stat3-/-oocytes, and oocyte maturation proceeded normally, suggesting that pStat3 was still functional. Furthermore, the treatment of oocytes with the Stat3-specific inhibitors stattic and BP-1-102 or anti-pStat3 antibody led to significantly abnormal spindle assembly and chromosome mislocation in a dose-dependent manner, and pStat3 was either absent or improperly localized in these oocytes. Moreover, the development of pre-implantation stage embryos derived from inhibitor-treated oocytes was significantly hampered following in vitro fertilization. These findings indicate a novel function of pStat3 in spindle assembly.//////////////////
STAT3 signaling stimulates miR-21 expression in bovine cumulus cells during in vitro oocyte maturation. Tscherner A et al. (2018) MicroRNAs are potent regulators of gene expression that have been widely implicated in reproduction and embryo development. Recent studies have demonstrated that miR-21, a microRNA extensively studied in the context of disease, is important in multiple facets of reproductive biology including folliculogenesis, ovulation, oocyte maturation and early mammalian development. Surprisingly, little is known about the mechanisms that regulate miR-21 and no studies have characterized these regulatory pathways in cumulus-oocyte complexes (COCs). We therefore investigated miR-21 in an in vitro model of bovine oocyte maturation. Levels of the primary transcript of miR-21 (pri-miR-21) and mature miR-21 increased markedly in COCs over the maturation period. Cloning of the bovine pri-miR-21 gene and promoter by 5'3'RACE (rapid amplification of cDNA ends) revealed a highly conserved region immediately upstream of the transcription start site and two alternatively-spliced variants of pri-miR-21. The promoter region contained several putative transcription factor binding sites, including two for signal transducer and activator of transcription 3 (STAT3). Mutation of these sites significantly decreased both the intrinsic activity of pri-miR-21 promoter-luciferase constructs and the response to leukemia inhibitory factor (LIF) (a STAT3 activator) in cultured MCF7 cells. In COCs, treatment with a STAT3 pathway inhibitor markedly decreased pri-miR-21 expression and prevented cumulus expansion. Pri-miR-21 expression was also inhibited by the protein synthesis inhibitor cycloheximide, suggesting that a protein ligand or signaling cofactor synthesized during maturation is necessary for transcription. Together these studies represent the first investigation of signaling pathways that directly influence miR-21 expression in bovine oocytes and cumulus cells.//////////////////
Leukemia Inhibitory Factor is Necessary for Ovulation in Female Rhesus Macaques. Murphy MJ et al. (2016) Although the requirement of pituitary-derived luteinizing hormone (LH) for ovulation is well documented, the intrafollicular paracrine and autocrine processes elicited by LH necessary for follicle rupture are not fully understood. Evaluating a published rhesus macaque periovulatory transcriptome database revealed that mRNA encoding leukemia inhibitory factor (LIF) and its downstream signaling effectors are upregulated in the follicle after animals receive an ovulatory stimulus (human chorionic gonadotropin; hCG). Follicular LIF mRNA and protein levels are below the limit of detection prior to the administration of hCG, but increase significantly 12 h thereafter. Downstream LIF receptor signaling components including interleukin-6 signal transducer (IL6ST), the receptor associated janus kinase (JAK) 1 and the transcription factor signal transducer and activator of transcription (STAT) 3 also exhibit increased expression in the rhesus macaque follicle 12 h after administration of an ovulatory hCG bolus. A laparoscopic ovarian evaluation 72 h after the injection of a LIF antagonist (soluble LIF receptor; sLIFR) into the rhesus macaque preovulatory follicle and hCG administration revealed blocking LIF action prevented ovulation (typically occurs 36 to 44 h post-hCG). Moreover, ovaries removed 52 h after both hCG and intrafollicular sLIFR administration confirmed ovulation was blocked as evidenced by the presence of an intact follicle and a trapped cumulus-oocyte complex. These findings give new insight into the role of LIF in the primate ovary and could lead to the development of new approaches for the control of fertility.//////////////////
Leukemia inhibitory factor promotes porcine oocyte maturation and is accompanied with activation of signal transducer and activator of transcription 3. Dang-Nguyen TQ 2013 et al.
We produced recombinant porcine leukemia inhibitory factor (pLIF) and examined its effect on in vitro maturation (IVM) of porcine oocytes and their developmental competence after in vitro fertilization. Porcine cumulus-oocyte complexes (COCs) were matured in a medium supplemented with pLIF during the first 22?h, last 22?h, or entire 44?h duration of IVM. Oocytes in all groups tended to show enhanced nuclear maturation rates by the metaphase II (MII) stage (76.1%, 82.1%, and 86.6%, respectively) compared to the without-pLIF treatment group (69.6%, control). A significant increase in MII rate (P?Khatib H et al. Infertility is a major cause of dairy cow culling and economic loss. Signal transducer and activator of transcription (STAT) proteins are transcription factors that play an important role in fertility and early embryonic development, among many other functions. Previous studies have reported the association of several genes from the JAK/STAT signaling pathway with fertility traits in cattle. The STAT1 and STAT3 genes are members of this pathway and are known to interact with each other by forming a heterodimer complex that enters the nucleus and controls expression of specific genes. Thus, the objective of this study was to investigate the effects of the interactions between polymorphisms in these genes on fertilization and early embryonic survival rates using an in vitro fertilization system. A total of 7,519 oocytes, collected from 445 ovaries, were exposed to sperm and a total of 5,075 embryos were produced. Fertilization rate was calculated as the number of cleaved embryos at 48 h post-fertilization out of the total number of oocytes exposed to sperm. Early embryonic survival rate of embryos was calculated as the number of blastocysts on d 7 of development out of the total number of embryos cultured. Effects of ovary genotypes on fertilization and early embryonic survival rates were evaluated. Single-SNP analysis revealed a statistically significant association between SNP25402 in STAT3 and fertilization rate. Oocytes produced from ovaries with AA genotype showed a 0.701 fertilization rate versus 0.666 and 0.663 for oocytes produced from AC and CC ovaries, respectively. The interaction between STAT3 SNP (SNP19069/SNP25402) was highly significant for survival rate but not for fertilization rate. Also, the interaction between STAT1 SNP and SNP19069 was highly significant for survival rate. Genotype combinations found to promote fertilization and embryonic survival could be incorporated into breeding programs aimed at improving fertility performance in dairy cattle.
Expression regulated by
Growth Factors/ cytokines, LIF
Comment
Cloning of porcine signal transducer and activator of transcription 3 cDNA and its expression in reproductive tissues. Wen L et al. The signal transducer and activator of transcription 3 (Stat3) protein is a member of the Stat family that has a variety of biological functions including cell growth, anti-apoptosis, and cell motility, depending on the cell type and stimulus. Recent studies have suggested that Stat3 plays an important role in embryo development. Although the Stat3 gene has been cloned in humans, mice, cow, and rats, its sequence in pigs is unknown. In the present study, the 2476 bp Stat3 cDNA was cloned using real time reverse transcriptase (RT)-PCR. Comparison of sequences across species revealed that the porcine Stat3 cDNA is 93 and 90% homologous to human and mouse respectively. To study the expression pattern of Stat3, RNA and protein were isolated from heart, lung, kidney, ovary, oviduct, and uterus tissues. RT-PCR and western blot indicated that Stat3 is expressed in all the tissues tested, and the level of expression is relatively high in tissues from the reproductive system. In addition, immunohistochemistry studies suggested that the Stat3 protein was present in the oocyte, granulosa, theca, and interstitial cells of the ovary, the mucosal folds in the oviduct, and both the epithelium and stromal layers in the endometrium. To study whether Stat3 is functional in responding to growth factor stimulation in the ovary, granulosa cells were isolated from large follicles (>3 mm) and cultured in the presence of epidermal growth factor (EGF; 10 ng/ml) for 5, 10, 15, 30, and 60 min, following which western blots were performed using an antibody against the phosphorylated Stat3. Phosphorylated Stat3 was upregulated following 5 min of EGF challenge and was sustained during the 15-min stimulation, and decreased back to the control level following 60-min stimulation. The translocation of phosphorylated Stat3 from cytoplasm to nucleus following stimulation of EGF was also detected via immunocytochemistry. Our data suggests that Stat3 may play a role in porcine ovarian function.
Ovarian localization
Oocyte, Cumulus, Granulosa, Theca, Stromal cells
Comment
Expression of Stat3 in germ cells of developing and adult mouse ovaries and testes Murphy K, et al .
The Signal transducers and activators of transcription (Stat) family of proteins plays diverse roles during differentiation in many tissues. Stat3 is an essential mammalian gene, critical during embryonic development. In mammals, Stat3 is differentially distributed in the cytoplasm of mature oocytes and in preimplantation embryos suggesting that Stat3 may be involved in determination of polarity. Here, we report that Stat3 protein is expressed in the cytoplasm of oocytes from primordial, primary and secondary follicles in the adult ovary and in developing acrosomes of round spermatids in the adult testis. Stat3 is also expressed in gonocytes, prospermatogonia, oogonia and oocytes of embryonic and neonatal gonads.
Association of Serum and Follicular Fluid Leptin Concentrations with Granulosa Cell p-STAT3 Expression in Fertile Patients with Polycystic Ovarian Syndrome. Mei-Gen L et al. Objectives: To evaluate whether polycystic ovarian syndrome (PCOS)-associated infertility is related to alterations of leptin, leptin receptor (Ob-R) and p-STAT3/SOCS3 system in the ovary. Design and setting: A case-control study conducted in a university hospital. Patients: Thirty-one infertile PCOS women with oligo-ovulation plus polycystic ovarian morphology and seventy-nine infertile women with tubal blockage (control). The subjects were stratified according to IVF outcomes: successful and failed subgroups. Methods: Serum and follicular fluid (FF) leptin levels were measured with ELISA. RT-PCR and Western blotting were performed to assess expression of mRNA encoding leptin and Ob-R and proteins of p-STAT3 and SOCS3 in granulosa cells (GCs). Results: Leptin levels in serum and FF of PCOS women were significantly higher than those of control (P<0.01). There were no significant differences in expression of leptin mRNA, short and long Ob-Rs between PCOS and control (P>0.05). P-STAT3 level was decreased in PCOS compared with control (P<0.01), whereas SOCS3 remained significantly unchanged (P>0.05). Further analysis showed that serum and FF leptin levels were significantly higher, while p-STAT3 in GCs was lower in failed subgroup of PCOS than those in successful subgroup of PCOS (P<0.05). Conclusion: Hyperleptinemia and high FF leptin are important pathologies of PCOS with infertility. Lower levels of p-STAT3 in GCs may be related to ovarian leptin resistance and fecundity in PCOS women. Relatively high serum and FF leptin and low p-STAT3 in GCs may account for decreased fertilization, implantation and pregnancy rates of IVF in PCOS women.
Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment: Identification of Sites of STAT3 Action in the Female Reproductive Tract through Conditional Gene Deletion. Robker RL 2014 et al.
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.
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