The Immp2l Mutation Causes Ovarian Aging Through ROS-Wnt/β-Catenin-Estrogen Pathway: Preventive Effect of Melatonin

Endocrinology ◽  
2020 ◽  
Vol 161 (9) ◽  
Author(s):  
Qing He ◽  
Lifang Gu ◽  
Qingyin Lin ◽  
Yi Ma ◽  
Chunlian Liu ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Granulosa Cells ◽  
Growth And Development ◽  
Steroid Hormone ◽  
Ovarian Follicle ◽  
Cell Aging ◽  
Follicle Growth ◽  
Melatonin Treatment ◽  
Hormone Synthesis ◽  
Ovarian Aging

Abstract Mitochondria play important roles in ovarian follicle development. Mitochondrial dysfunction, including mitochondrial gene deficiency, impairs ovarian development. Here, we explored the role and mechanism of mitochondrial inner membrane gene Immp2l in ovarian follicle growth and development. Our results revealed that female Immp2l-/- mice were infertile, whereas Immp2l+/- mice were normal. Body and ovarian weights were reduced in the female Immp2l-/- mice, ovarian follicle growth and development were stunted in the secondary follicle stage. Although a few ovarian follicles were ovulated, the oocytes were not fertilized because of mitochondrial dysfunction. Increased oxidative stress, decreased estrogen levels, and altered genes expression of Wnt/β-catenin and steroid hormone synthesis pathways were observed in 28-day-old Immp2l-/- mice. The Immp2l mutation accelerated ovarian aging process, as no ovarian follicles were detected by age 5 months in Immp2l-/- mice. All the aforementioned changes in the Immp2l-/- mice were reversed by administration of antioxidant melatonin to the Immp2l-/- mice. Furthermore, our in vitro study using Immp2l knockdown granulosa cells confirmed that the Immp2l downregulation induced granulosa cell aging by enhancing reactive oxygen species (ROS) levels, suppressing Wnt16, increasing β-catenin, and decreasing steroid hormone synthesis gene cyp19a1 and estrogen levels, accompanied by an increase in the aging phenotype of granulosa cells. Melatonin treatment delayed granulosa cell aging progression. Taken together, Immp2l causes ovarian aging through the ROS-Wnt/β-catenin-estrogen (cyp19a1) pathway, which can be reversed by melatonin treatment.

miR-130a-3p regulates steroid hormone synthesis in goat ovarian granulosa cells by targeting the PMEPA1 gene

2021 ◽  
Vol 165 ◽  
pp. 92-98
Author(s):  
Lu Zhu ◽  
Jing Jing ◽  
Shuaiqi Qin ◽  
Qi Zheng ◽  
Jiani Lu ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Steroid Hormone ◽  
Hormone Synthesis ◽  
Ovarian Granulosa Cells

MiR-31 and miR-143 affect steroid hormone synthesis and inhibit cell apoptosis in bovine granulosa cells through FSHR

2019 ◽  
Vol 123 ◽  
pp. 45-53 ◽  
Author(s):  
Zhe Zhang ◽  
Cheng-Zhen Chen ◽  
Ming-Qiang Xu ◽  
Li-Qun Zhang ◽  
Jian-Bo Liu ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Cell Apoptosis ◽  
Steroid Hormone ◽  
Hormone Synthesis

Raf‐ERK1/2 signalling pathways mediate steroid hormone synthesis in bovine ovarian granulosa cells

2019 ◽  
Vol 54 (5) ◽  
pp. 741-749 ◽  
Author(s):  
Dejun Xu ◽  
Huanshan He ◽  
Xiaohan Jiang ◽  
Lulu Yang ◽  
Dinbang Liu ◽  
...  
Keyword(s):  
Granulosa Cells ◽  
Steroid Hormone ◽  
Signalling Pathways ◽  
Hormone Synthesis ◽  
Ovarian Granulosa Cells

268. Suppressors of cytokine signalling (SOCS): roles in ovarian follicle activation

2008 ◽  
Vol 20 (9) ◽  
pp. 68
Author(s):  
R. Keightley ◽  
E. McLaughlin ◽  
S. D. Roman ◽  
R. L. Robker ◽  
D. L. Russell
Keyword(s):  
Granulosa Cells ◽  
Ovarian Follicle ◽  
Expression Patterns ◽  
Neonatal Mouse ◽  
Mrna Levels ◽  
Follicle Growth ◽  
Oocyte Growth ◽  
Primordial Follicles ◽  
Gene And Protein Expression ◽  
Follicle Activation

Oocytes are sequestered in primordial follicles before birth and remain quiescent in the ovary for decades, until recruited into the growing pool throughout the reproductive years. Therefore activation of follicle growth is a major biological checkpoint that controls female reproductive potential. However we are only just beginning to elucidate the cellular mechanisms required, for either maintenance of the quiescent primordial pool, or initiation of follicle growth. Analysis of microarray data derived from neonatal mouse ovaries indicated that members of the Suppressors of Cytokine Signalling SOCS family of proteins may play pivotal roles in folliculogenesis. We undertook a detailed analysis of gene and protein expression patterns of the eight members of the SOCS family, namely CIS and SOCS1–7, within adult and neonatal mouse ovaries. Quantitative real time PCR and immunohistochemistry was performed to determine mRNA levels and cellular localisation in the ovaries of cycling and new born animals. SOCS proteins were expressed largely within the oocytes of developing follicles and in the granulosa cells of the larger preovulatory follicles. Expression of SOCS4 in the granulosa cells and SOCS5 within the oocyte was coincident with the activation of oocyte growth and the differentiation of squamous pregranulosa to cuboidal granulosa cells. Our investigation has identified a role for the SOCS family proteins within the ovary and SOCS4 and SOCS5 as major regulators of cytokine signalling pathways in follicle activation and development.

Melatonin potentially acts directly on swine ovary by modulating granulosa cell function and angiogenesis

2017 ◽  
Vol 29 (12) ◽  
pp. 2305 ◽  
Author(s):  
Giuseppina Basini ◽  
Simona Bussolati ◽  
Roberta Ciccimarra ◽  
Francesca Grasselli
Keyword(s):  
Granulosa Cell ◽  
Granulosa Cells ◽  
Cell Function ◽  
Ovarian Follicle ◽  
Hormone Release ◽  
Follicle Growth ◽  
Reproductive Effects ◽  
Vessel Growth ◽  
Gonadotrophin Releasing Hormone ◽  
Local Modulation

Melatonin exerts well-known reproductive effects, mainly acting on hypothalamic gonadotrophin-releasing hormone release. More recent data suggest that melatonin acts directly at the ovarian level, even if, at present, these aspects have been only partly investigated. Swine follicular fluid contains melatonin and its concentration is significantly reduced during follicular growth. Therefore, the present study was undertaken to examine the effects of melatonin, used at physiological concentrations, on cultured swine granulosa cells collected from small (<3 mm) and large (>5 mm) follicles on the main parameters of granulosa cell function such as proliferation and steroidogenesis, namely oestradiol 17β and progesterone (P4) production. Moreover, the effects of melatonin on superoxide anion and nitric oxide (NO) generation by swine granulosa cells were also investigated. Finally, since angiogenesis is crucial for follicle growth, the effects of melatonin on new vessel growth were studied. Collected data indicate that melatonin interferes with cultured granulosa cell proliferation and steroidogenesis, specifically in terms of P4 production and NO output. In addition, the events of physiological follicular angiogenesis were stimulated by melatonin as evidenced by angiogenesis bioassay. Therefore, we suggest that physiological melatonin concentrations could potentially be involved in local modulation of swine ovarian follicle function.

scholarly journals The Mechanism of Melatonin and Its Receptor MT2 Involved in the Development of Bovine Granulosa Cells

2018 ◽  
Vol 19 (7) ◽  
pp. 2028 ◽  
Author(s):  
Shujuan Wang ◽  
Wenju Liu ◽  
Xunsheng Pang ◽  
Sifa Dai ◽  
Guodong Liu
Keyword(s):  
Granulosa Cells ◽  
Regulatory Mechanism ◽  
Steroid Hormone ◽  
Inhibin B ◽  
Critical Approach ◽  
Hormone Synthesis ◽  
Ovarian Granulosa Cells ◽  
Genes Expression ◽  
Significant Difference

Ovarian granulosa cells (GCs) are a critical approach to investigate the mechanism of gene regulation during folliculogenesis. The objective of this study was to investigate the role of MT2 in bovine GCs, and assess whether MT2 silencing affected GCs response to melatonin. We found that MT2 silencing significantly decreased the secretion of progesterone and estradiol, and increased the concentration of inhibin B and activin B. To further reveal the regulatory mechanism of MT2 silencing on steroids synthesis, it was found that the expression of CYP19A1 and CYP11A1 enzymes (steroid hormone synthesis) were down-regulated, while genes related to hormonal synthesis (StAR, RUNX2, INHA and INHBB) were up-regulated without affecting the expression of INHBA, suggesting that MT2 silencing may regulate hormone abundance. Furthermore, MT2 silencing significantly increased the expression of TGFBR3 and BMP6, and decreased the expression of LHR and DNMT1A without significant difference in the expression of FSHR and EGFR. In addition, MT2 silencing didn’t affect the effect of melatonin on increasing the expression of DNMT1A, EGFR, INHBA and LHR, and progesterone level, or decreasing INHA, TGFBR3 and StAR expression, and production of inhibin B. Moreover, MT2 silencing could disrupt the role of melatonin in decreasing the FSHR, INHBB and BMP6 expression, and activin B secretion. In conclusion, these results reveal that melatonin and MT2 are essential regulator of bovine GCs function by modulating reproduction-related genes expression, hormones secretion and other regulators of folliculogenesis.

scholarly journals The selective prostaglandin EP4 agonist, APS-999 Na, induces follicular growth and maturation in the rat ovary

2005 ◽  
Vol 152 (2) ◽  
pp. 315-323 ◽  
Author(s):  
Nagwa El-Nefiawy ◽  
Khaled Abdel-Hakim ◽  
Naohiro Kanayama
Keyword(s):  
Growth And Development ◽  
Ovarian Follicle ◽  
Morphological Characteristics ◽  
Dependent Manner ◽  
Follicle Growth ◽  
Promoting Effect ◽  
Ep4 Receptor ◽  
Rat Ovary ◽  
Ovulatory Follicles

Objective: It is known that prostaglandin E2 (PGE2) plays a crucial role in the ovulation process. PGE2 mediates its actions through four subtypes of receptors designated EP1–EP4. However, the nature of the ovulation-promoting effect of PGE2 is not well understood. We have carried out this in vivo research utilizing a new selective EP4 receptor agonist (EP4A; APS-999 Na) to investigate its role in folliculogenesis aiming at more understanding of the biological mechanism of action of PGE2. Design and methods: Immature, 22 day old Wistar rats were used. Animals were injected once either with placebo, 20 IU pregnant mare serum gonadotrophin (PMSG), or EP4A (10, 20 or 50 μg). In other experiments, EP4A was injected in PMSG stimulated rats. Ovarian follicle growth and development was assessed through total count and size measurement of ovulatory follicles in whole ovaries of the investigated groups. Utilizing immunohistochemistry, the spatial localization of the EP4 receptor in immature rat ovary and IL-8 pattern of expression after EP4A injection was also investigated. Results: Our study showed that injection of EP4A resulted in increased follicle growth and development compared with the control, in a time- and dose-dependent manner. The highest values for follicle count and size were observed 12 and 24 h after EP4A injection. EP4A induced follicle growth with morphological characteristics similar to that induced by the standard PMSG. Most dense immune staining for EP4 receptor was noticed in proliferating granulosa cells of the secondary follicles while those of the primordial and primary follicles were not stained. EP4A injection induced the expression of IL-8 in the follicles. Conclusions: Our study revealed that: (i) the localization of EP4 receptor in the ovary implies a role in follicle growth, (ii) PGE2 induced ovarian follicle growth and development is mediated at least in part through the EP4 receptor, (iii) the action of EP4A is mediated through IL-8 up regulation and (iv) the new EP4A could be a promising reagent for various systems used to induce follicle maturation in clinical or agricultural fields. This knowledge may provide useful targets for manipulation of infertility.

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