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Search for other papers by Fang-Ju Wu in
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Search for other papers by Ying-Wen Wang in
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Bone morphogenetic proteins (BMPs) are known to play an indispensable role in preventing the precocious luteinization of granulosa cells within growing ovarian follicles. In this study, we found that the transcripts of BMP8 genes are enriched in the ovaries of humans and rodents. When analyzing transcriptomic datasets obtained from human mature granulosa cells, we further found that the BMP8 transcripts not only show the highest abundance among the searchable BMP-related ligands but also decrease significantly in women of advanced age or women with polycystic ovarian syndrome. The correlation between the BMP8 levels in granulosa cells and the decline in ovarian function in these subjects suggests that BMP8 protein may be involved in the regulation of granulosa cell function(s). Using a rat model, we demonstrated that human BMP8A protein activates the SMAD1/5/8 and the SMAD2/3 pathways simultaneously in both immature and mature granulosa cells. Furthermore, the expression of potential type I and type II receptors used by BMP8 in rat granulosa cells was characterized. We found that BMP8A treatment can significantly inhibit gonadotropin-induced progesterone production and steroidogenesis-related gene expression in granulosa cells. Pathway dissection using receptor inhibitors further revealed that such inhibitory effects occur specifically through the BMP8-activated SMAD1/5/8, but not SMAD2/3, pathway. Taken together, considering its abundance and possible functions in granulosa cells, we suggest that BMP8 may act as a novel luteinization inhibitor in growing follicles.
Reproductive Medicine Center, The People’s Hospital of Zhengzhou University, Henan Provincial People’s Hospital, Zhengzhou, Henan, China
Search for other papers by Huijuan Zhang in
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Search for other papers by Guishuan Wang in
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Search for other papers by Lin Liu in
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Search for other papers by Chu-Fang Chou in
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The chromatoid body (CB) is a specific cloud-like structure in the cytoplasm of haploid spermatids. Recent findings indicate that CB is identified as a male germ cell-specific RNA storage and processing center, but its function has remained elusive for decades. In somatic cells, KH-type splicing regulatory protein (KSRP) is involved in regulating gene expression and maturation of select microRNAs (miRNAs). However, the function of KSRP in spermatogenesis remains unclear. In this study, we showed that KSRP partly localizes in CB, as a component of CB. KSRP interacts with proteins (mouse VASA homolog (MVH), polyadenylate-binding protein 1 (PABP1) and polyadenylate-binding protein 2 (PABP2)), mRNAs (Tnp2 and Odf1) and microRNAs (microRNA-182) in mouse CB. Moreover, KSRP may regulate the integrity of CB via DDX5-miRNA-182 pathway. In addition, we found abnormal expressions of CB component in testes of Ksrp-knockout mice and of patients with hypospermatogenesis. Thus, our results provide mechanistic insight into the role of KSRP in spermatogenesis.
Search for other papers by Da Li in
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Search for other papers by Yue You in
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Search for other papers by Fang-Fang Bi in
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Search for other papers by Tie-Ning Zhang in
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Search for other papers by Jiao Jiao in
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Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, USA
Search for other papers by Tian-Ren Wang in
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Search for other papers by Yi-Ming Zhou in
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Search for other papers by Zi-Qi Shen in
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Search for other papers by Xiu-Xia Wang in
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Search for other papers by Qing Yang in
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The importance of autophagy in polycystic ovary syndrome (PCOS)-related metabolic disorders is increasingly being recognized, but few studies have investigated the role of autophagy in PCOS. Here, transmission electron microscopy demonstrated that autophagy was enhanced in the ovarian tissue from both humans and rats with PCOS. Consistent with this, ovarian granulosa cells from PCOS rats showed increases in the autophagy marker protein light chain 3B (LC3B), whereas levels of the autophagy substrate SQSTM1/p62 were decreased. In addition, the ratio of LC3-II/LC3-I was markedly elevated in human PCOS ovarian tissue compared with normal ovarian tissue. Real-time PCR arrays indicated that 7 and 34 autophagy-related genes were down- and up-regulated in human PCOS , Signal-Net, and regression analysis suggested that there are a wide range of interactions among these 41 genes, and a potential network based on EGFR, ERBB2, FOXO1, MAPK1, NFKB1, IGF1, TP53 and MAPK9 may be responsible for autophagy activation in PCOS. Systematic functional analysis of 41 differential autophagy-related genes indicated that these genes are highly involved in specific cellular processes such as response to stress and stimulus, and are linked to four significant pathways, including the insulin, ERBB, mTOR signaling pathways and protein processing in the endoplasmic reticulum. This study provides evidence for a potential role of autophagy disorders in PCOS in which autophagy may be an important molecular event in the pathogenesis of PCOS.
Search for other papers by Ning Wang in
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Search for other papers by Liya Wang in
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Search for other papers by Fang Le in
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Search for other papers by Qitao Zhan in
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Search for other papers by Yingming Zheng in
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Search for other papers by Guolian Ding in
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Despite the efforts to recapitulate the follicle environment, oocytes from in vitro maturation (IVM) have poorer developmental potential than those matured in vivo and the effects on the resultant offspring are of concern. The aim of this study was to determine altered gene expression in oocytes following IVM and to evaluate the expression of the arginine rich, mutated in early stage of tumors gene (Armet) and mitochondrial ribosomal protein L51 (Mrpl51) in embryos and brains of fetal/postnatal mice and the brain development of IVM offspring. An IVM mouse model was established while oocytes matured in vivo were used as the controls. Suppressive subtractive hybridization (SSH) and RT-PCR/western blot were used to analyze the differential expression of genes/proteins between IVM and the control group. HE staining and water maze were used to assess the histological changes in brain tissue and cognition of the offspring. The rates of fertilization, cleavage, and live birth were significantly decreased in IVM group. Thirteen genes were upregulated in IVM oocytes compared with the control, including Armet and Mrpl51. The higher level of Armet in IVM oocytes was retained in brain of newborn mice, which could be related to the upregulation of activating transcription factor 6 (Atf6) and X-box binding protein 1 (Xbp1), while Mrpl51 was expressed normally in brain of postnatal mice. No significant differences were detected in brain weight, neuronal counts, and the cognition in the offspring between the two groups. The present results suggested that IVM could affect the pregnancy outcome and the Armet and Mrpl51 gene/protein expression. The change in Armet expression lasted while the change of Mrpl51 disappeared after birth. However, the brain development of the offspring seemed to be unaffected by IVM.
Search for other papers by Xihua Chen in
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Search for other papers by Bin Wu in
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Search for other papers by Shufang Wang in
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Search for other papers by Jianbing Liu in
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Search for other papers by Haijun Gao in
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Male Clinical Laboratory, National Research Institute for Family Planning, Beijing, People’s Republic of China
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Peking Union Medical College, Beijing, People’s Republic of China
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Peking Union Medical College, Beijing, People’s Republic of China
Search for other papers by Bonan Zhang in
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Search for other papers by Jiedong Wang in
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Search for other papers by Bin He in
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Menstruation is a specific physiological phenomenon that occurs in women. However, molecular mechanisms underlying this phenomenon are still unclear. According to the classical theory, tissue hypoxia resulting from vasoconstriction of the spiral arteries after progesterone (P4) withdrawal initiates the breakdown of the endometrium at the earliest stage of menstruation. However, this theory has been challenged by previous studies that have questioned the function and even the existence of hypoxia during menstruation. In this study, we not only provide convincing evidence that hypoxia exists during endometrial breakdown, but also further explore the role of hypoxia and hypoxia-inducible factor 1 (HIF1) in this process. Based on mouse menstrual-like model and experiments with human decidual stromal cells, we observed that P4 withdrawal induced both hypoxia and HIF1 activation; however, endometrial breakdown was triggered only by P4 withdrawal. Hypoxia significantly enhanced the mRNA expression of specific matrix metalloproteinases (MMPs) under the conditions of P4 withdrawal. In conclusion, hypoxia is involved but not an essential component of endometrial breakdown during menstruation.
Search for other papers by Kun Lei in
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Search for other papers by Quanwei Wei in
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Search for other papers by Ying Cheng in
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Search for other papers by Zhe Wang in
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Search for other papers by Haoze Wu in
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Search for other papers by Fang Zhao in
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Search for other papers by Wei Ding in
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Search for other papers by Fangxiong Shi in
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In brief
The apoptosis of granulosa cells (GCs) is the main reason for porcine follicular atresia. This study provides a novel mechanism for peroxynitrite anion-mediated GC apoptosis and follicular atresia in porcine ovary.
Abstract
Granulosa cells play a crucial role in the development of follicles, and their cell apoptosis in the porcine ovary is a major contributor to follicular atresia. Here, we provide a new mechanism for follicular atresia by describing a crucial mechanism by which peroxynitrite anion (OONO–) may cause GC death. We discovered that nitric oxide, oxidative stress level, and OONO– were positively correlated with porcine follicular atresia, which was accompanied by high expression of matrix metalloproteinase 2 (MMP2) and MMP9. We created a model of OONO–-induced apoptosis in GCs and discovered that OONO– could boost the expression of MMP2 and MMP9 and increase the expression of pro-apoptotic proteins and DNA damage. Furthermore, by inhibiting the activities of MMP2 and MMP9, we found that SB-3CT (a specific inhibitor for MMP2 and MMP9) alleviated the decrease in cell survival rates and DNA damage caused by OONO–, which may have been impacted by reducing the cleavage of PARP1 by MMP2 and MMP9. Therefore, our findings imply that OONO– can cause DNA damage to GCs, participating in mediating the expression of pro-apoptotic proteins and inhibiting DNA repair by preventing the activity of PARP1 through MMP2 and MMP9. These results help explain how OONO–/MMP2/MMP9 affects porcine follicular atresia and GC apoptosis.
Search for other papers by Fang Yang in
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Shanghai First Maternity and Infant Hospital, Epithelial Cell Biology Research Centre, Shenzhen Research Institute, School of Medicine, Tongji University, Shanghai, China
Search for other papers by Ye-Chun Ruan in
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Search for other papers by Yun-jie Yang in
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Search for other papers by Kai Wang in
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Search for other papers by Shan-shan Liang in
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Search for other papers by Yi-bin Han in
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Search for other papers by Xiao-Ming Teng in
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Search for other papers by Jian-Zhi Yang in
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Women with polycystic ovary syndrome (PCOS) undergoing IVF–embryo transfer based-assisted reproductive technology (ART) treatment show variable ovarian responses to exogenous FSH administration. For better understanding and control of PCOS ovarian responses in ART, the present study was carried out to compare the follicular hormones and the expression of granulosa cell genes between PCOS and non-PCOS women during ART treatment as well as their IVF outcomes. Overall, 138 PCOS and 78 non-PCOS women were recruited for the present study. Follicular fluid collected from PCOS women showed high levels of testosterone. The expression of aromatase was found significantly reduced in luteinized granulosa cells from PCOS women. In cultured luteinized granulosa cells isolated from non-PCOS women, their exposure to testosterone at a level that was observed in PCOS follicles could decrease both mRNA and protein levels of aromatase in vitro. The inhibitory effect of testosterone was abolished by androgen receptor antagonist, flutamide. These results suggest that the hyperandrogenic follicular environment may be a key hazardous factor leading to the down-regulation of aromatase in PCOS.
Search for other papers by Guoyun Wu in
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Search for other papers by Dan Song in
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Search for other papers by Huadong Wu in
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Search for other papers by Fang Zhao in
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Search for other papers by Wei Ding in
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Search for other papers by Zhe Wang in
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Search for other papers by Fangxiong Shi in
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Search for other papers by Quanwei Wei in
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In brief
Genistein contributes to granulosa cell (GC) survival by two routes: one is that genistein induced p-AMPK and inhibited p-mTOR, which induces LC3 activation and autophagy; the other is that genistein inhibited caspase-3 and its cleavage, which induces PARP1 activation and PARylation.
Abstract
Genistein is an isoflavone which is beneficial for health, but little is known regarding its function on granulosa cell fate during follicular atresia. In the present study, we established an in vitro model of porcine follicular granulosa cell apoptosis by serum deprivation and showed that treatments with 1 μM and 10 μM genistein significantly reduced the apoptotic rate of granulosa cells compared to the blank control (P < 0.05). These results suggest that genistein at micromolar levels alleviates serum deprivation-induced granulosa cell apoptosis, and the ameliorative effect of genistein on granulosa cell apoptosis is likely to be able to inhibit nutrient depletion-induced follicular atresia. Further experimental results revealed that the expression of the autophagic marker protein LC3II in 100 nM–10 μM genistein treatment increased in a dose-dependent manner and was higher than the control (P < 0.05). Genistein also dose dependently promoted the phosphorylation of AMPK (adenosine 5’-monophosphate-activated protein kinase) in granulosa cells. Poly(ADP-ribose) (pADPr) formation in genistein-treated groups was also notably higher than in the controls (P < 0.05). Collectively, genistein alleviates serum deprivation-induced granulosa cells in vitro through enhancing autophagy, which involving AMPK activation and PARylation signaling. However, further study should be carried out to investigate the role of the aforementioned signaling on this process.
Search for other papers by Jiarui Wei in
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Search for other papers by Xing Lan An in
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Search for other papers by Cong Fu in
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Search for other papers by Qi Li in
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Search for other papers by Fang Wang in
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Search for other papers by Rong Huang in
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Search for other papers by Haibo Zhu in
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Search for other papers by Ziyi Li in
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Search for other papers by Sheng Zhang in
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Thousands of genes are activated in late 2-cell embryos, which means that numerous pre-mRNAs are generated during this time. These pre-mRNAs must be accurately spliced to ensure that the mature mRNAs are translated to functional proteins. However, little is known about the roles of pre-mRNA splicing and cellular factors modulating pre-mRNA splicing during early embryonic development. Here, we report that downregulation of SON, a large Ser/Arg (SR)-related protein, reduced embryonic development and caused deficient blastomere cleavage. These embryonic developmental defects result from dysregulated nuclear speckle organization and pre-mRNA splicing of a set of cell cycle-related genes. Furthermore, SON downregulation disrupted the transcriptome (2128 upregulated and 1399 downregulated) in 4-cell embryos. Increased H3K4me3, H3K9me3 and H3K27me3 levels were detected in 4-cell embryos after SON downregulation. Taken together, these results demonstrate that accurate pre-mRNA splicing is essential for early embryonic development and that SON plays important roles in nuclear speckle organization, pre-mRNA splicing, transcriptome establishment and histone methylation reprogramming during early embryonic development.
Search for other papers by Hong-Lan Song in
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Department of Bioinformatics, School of Basic Medicine, Chongqing Medical University, Chongqing, China
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Search for other papers by Fang-Fang Li in
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Search for other papers by Enoch Appiah Adu-Gyamfi in
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The Joint International Research Laboratory of Reproduction and Development, Ministry of Education, Chongqing, China
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The Joint International Research Laboratory of Reproduction and Development, Ministry of Education, Chongqing, China
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Department of Herbal Medicine, School of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, China
Department of Herbal Medicine, School of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, China
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The syncytiotrophoblast, derived from cytotrophoblast fusion, is responsible for maternal–fetal exchanges, secretion of pregnancy-related hormones, and fetal defense against pathogens. Inadequate cytotrophoblast fusion can lead to pregnancy disorders, such as preeclampsia and fetal growth restriction. However, little is known about the mechanism of cytotrophoblast fusion in both physiological and pathological pregnancy conditions. In this study, P57kip2 (P57), a cell cycle-dependent kinase inhibitor that negatively regulates the cell cycle, was found to be up-regulated during the process of syncytialization in both primary trophoblast cells and BeWo cells. Co-immunofluorescence with proliferation markers Ki67 and Cyclin-CDK factors further showed that P57 specifically localizes in the post-mitotic cytotrophoblast subtype of the early pregnancy villi. Overexpression of P57 promoted trophoblast syncytialization by arresting the cell cycle at the G1/G0 phase and inhibiting proliferation. Blocking of the cell cycle through a serum starvation culture resulted in an enhancement of cytotrophoblast fusion and the up-regulation of P57. In both spontaneous cytotrophoblast fusion and forskolin-induced BeWo cell fusion models, an initial up-regulation of P57 was observed followed by a subsequent down-regulation. These findings indicate that proper expression of P57 at cytotrophoblast differentiation nodes plays an important role in trophoblast syncytialization.
