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Michael K Skinner - One of the best experts on this subject based on the ideXlab platform.
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Cytokine (IL16) and tyrphostin actions on ovarian Primordial Follicle development
Reproduction, 2014Co-Authors: Amanda Feeney, Eric E Nilsson, Michael K SkinnerAbstract:An ovarian Follicle is composed of an oocyte and surrounding theca and granulosa cells. Oocytes are stored in an arrested state within Primordial Follicles until they are signaled to re-initiate development by undergoing Primordial to primary Follicle transition. Previous gene bionetwork analyses of Primordial Follicle development identified a number of critical cytokine signaling pathways and genes potentially involved in the process. In the current study, candidate regulatory genes and pathways from the gene network analyses were tested for their effects on the formation of Primordial Follicles (Follicle assembly) and on Primordial Follicle transition using whole ovary organ culture experiments. Observations indicate that the tyrphostin inhibitor BCI increased Follicle assembly significantly, supporting a role for the mitogen activated protein kinase (MAPK) signaling pathway in Follicle assembly. The cytokine interleukin 16 (IL16) promotes Primordial to primary Follicle transition as compared to the controls, where as Delta-like 4 (DLL4) and WNT-3A treatment have no effect. Immunohistochemical experiments demonstrated for both the cytokine IL16 and its receptor CD4 localization to the granulosa cells surrounding each oocyte within the ovarian Follicle. The tyrphostin LDN193189 (LDN) is an inhibitor of the bone morphogenic protein receptor 1 (BMPR1) within the TGFB signaling pathway and was found to promote the Primordial to primary Follicle transition. Observations support the importance of cytokines (i.e. IL16) and cytokine signaling pathways in regulating early Follicle development. Insights into regulatory factors affecting early Primordial Follicle development are provided that may associate with ovarian disease and translate to improved therapy in the future.
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gene bionetworks that regulate ovarian Primordial Follicle assembly
BMC Genomics, 2013Co-Authors: Eric E Nilsson, Bin Zhang, Michael K SkinnerAbstract:Primordial Follicle assembly is the process by which ovarian Primordial Follicles are formed. During Follicle assembly oocyte nests break down and a layer of pre-granulosa cells surrounds individual oocytes to form Primordial Follicles. The pool of Primordial Follicles formed is the source of oocytes for ovulation during a female’s reproductive life. The current study utilized a systems approach to detect all genes that are differentially expressed in response to seven different growth factor and hormone treatments known to influence (increase or decrease) Primordial Follicle assembly in a neonatal rat ovary culture system. One novel factor, basic fibroblast growth factor (FGF2), was experimentally determined to inhibit Follicle assembly. The different growth factor and hormone treatments were all found to affect similar physiological pathways, but each treatment affected a unique set of differentially expressed genes (signature gene set). A gene bionetwork analysis identified gene modules of coordinately expressed interconnected genes and it was found that different gene modules appear to accomplish distinct tasks during Primordial Follicle assembly. Predictions of physiological pathways important to Follicle assembly were validated using ovary culture experiments in which ERK1/2 (MAPK1) activity was increased. A number of the highly interconnected genes in these gene networks have previously been linked to primary ovarian insufficiency (POI) and polycystic ovarian disease syndrome (PCOS). Observations have identified novel factors and gene networks that regulate Primordial Follicle assembly. This systems biology approach has helped elucidate the molecular control of Primordial Follicle assembly and provided potential therapeutic targets for the treatment of ovarian disease.
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inhibitory actions of anti mullerian hormone amh on ovarian Primordial Follicle assembly
PLOS ONE, 2011Co-Authors: Eric E Nilsson, Ryan Schindler, Marina I Savenkova, Michael K SkinnerAbstract:The current study was designed to investigate the actions of Anti-Mullerian Hormone (AMH) on Primordial Follicle assembly. Ovarian Primordial Follicles develop from the breakdown of oocyte nests during fetal development for the human and immediately after birth in rodents. AMH was found to inhibit Primordial Follicle assembly and decrease the initial Primordial Follicle pool size in a rat ovarian organ culture. The AMH expression was found to be primarily in the stromal tissue of the ovaries at this period of development, suggesting a stromal-epithelial cell interaction for Primordial Follicle assembly. AMH was found to promote alterations in the ovarian transcriptome during Primordial Follicle assembly with over 200 genes with altered expression. A gene network was identified suggesting a potential central role for the Fgf2/Nudt6 antisense transcript in the Follicle assembly process. A number of signal transduction pathways are regulated by AMH actions on the ovarian transcriptome, in particular the transforming growth factor – beta (TGFs) signaling process. AMH is the first hormone/protein shown to have an inhibitory action on Primordial Follicle assembly. Due to the critical role of the Primordial Follicle pool size for female reproduction, elucidation of factors, such as AMH, that regulate the assembly process will provide insights into potential therapeutics to manipulate the pool size and female reproduction.
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induction of ovarian Primordial Follicle assembly by connective tissue growth factor ctgf
PLOS ONE, 2010Co-Authors: Ryan Schindler, Eric E Nilsson, Michael K SkinnerAbstract:Primordial Follicle assembly is a process that occurs when oocyte nests break down to form individual Primordial Follicles. The size of this initial pool of Primordial Follicles in part determines the reproductive lifespan of the female. Connective tissue growth factor (CTGF) was identified as a potential regulatory candidate for this process in a previous microarray analysis of Follicle development. The current study examines the effects of CTGF and associated transforming growth factor beta 1 (TGFβ-1) on Follicle assembly. Ovaries were removed from newborn rat pups and placed in an organ culture system. The ovaries treated with CTGF for two days were found to have an increased proportion of assembled Follicles. CTGF was found to regulate the ovarian transcriptome during Primordial Follicle assembly and an integrative network of genes was identified. TGFβ-1 had no effect on Primordial Follicle assembly and in combination with CTGF decreased oocyte number in the ovary after two days of culture. Over ten days of treatment only the combined treatment of CTGF and TGFβ-1 was found to cause an increase in the proportion of assembled Follicles. Interestingly, treatment with TGFβ-1 alone resulted in fewer total oocytes in the ovary and decreased the Primordial Follicle pool size after ten days of culture. Observations indicate that CTGF alone or in combination with TGFβ-1 stimulates Primordial Follicle assembly and TGFβ-1 can decrease the Primordial Follicle pool size. These observations suggest the possibility of manipulating Primordial Follicle pool size and influencing female reproductive lifespan.
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gene bionetwork analysis of ovarian Primordial Follicle development
PLOS ONE, 2010Co-Authors: Eric E Nilsson, Bin Zhang, Ryan Schindler, Marina I Savenkova, Eric E Schadt, Michael K SkinnerAbstract:Ovarian Primordial Follicles are critical for female reproduction and comprise a finite pool of gametes arrested in development. A systems biology approach was used to identify regulatory gene networks essential for Primordial Follicle development. Transcriptional responses to eight different growth factors known to influence Primordial Follicles were used to construct a bionetwork of regulatory genes involved in rat Primordial Follicle development. Over 1,500 genes were found to be regulated by the various growth factors and a network analysis identified critical gene modules involved in a number of signaling pathways and cellular processes. A set of 55 genes was identified as potential critical regulators of these gene modules, and a sub-network associated with development was determined. Within the network two previously identified regulatory genes were confirmed (i.e., Pdgfa and Fgfr2) and a new factor was identified, connective tissue growth factor (CTGF). CTGF was tested in ovarian organ cultures and found to stimulate Primordial Follicle development. Therefore, the relevant gene network associated with Primordial Follicle development was validated and the critical genes and pathways involved in this process were identified. This is one of the first applications of network analysis to a normal developmental process. These observations provide insights into potential therapeutic targets for preventing ovarian disease and promoting female reproduction.
Eric E Nilsson - One of the best experts on this subject based on the ideXlab platform.
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Cytokine (IL16) and tyrphostin actions on ovarian Primordial Follicle development
Reproduction, 2014Co-Authors: Amanda Feeney, Eric E Nilsson, Michael K SkinnerAbstract:An ovarian Follicle is composed of an oocyte and surrounding theca and granulosa cells. Oocytes are stored in an arrested state within Primordial Follicles until they are signaled to re-initiate development by undergoing Primordial to primary Follicle transition. Previous gene bionetwork analyses of Primordial Follicle development identified a number of critical cytokine signaling pathways and genes potentially involved in the process. In the current study, candidate regulatory genes and pathways from the gene network analyses were tested for their effects on the formation of Primordial Follicles (Follicle assembly) and on Primordial Follicle transition using whole ovary organ culture experiments. Observations indicate that the tyrphostin inhibitor BCI increased Follicle assembly significantly, supporting a role for the mitogen activated protein kinase (MAPK) signaling pathway in Follicle assembly. The cytokine interleukin 16 (IL16) promotes Primordial to primary Follicle transition as compared to the controls, where as Delta-like 4 (DLL4) and WNT-3A treatment have no effect. Immunohistochemical experiments demonstrated for both the cytokine IL16 and its receptor CD4 localization to the granulosa cells surrounding each oocyte within the ovarian Follicle. The tyrphostin LDN193189 (LDN) is an inhibitor of the bone morphogenic protein receptor 1 (BMPR1) within the TGFB signaling pathway and was found to promote the Primordial to primary Follicle transition. Observations support the importance of cytokines (i.e. IL16) and cytokine signaling pathways in regulating early Follicle development. Insights into regulatory factors affecting early Primordial Follicle development are provided that may associate with ovarian disease and translate to improved therapy in the future.
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gene bionetworks that regulate ovarian Primordial Follicle assembly
BMC Genomics, 2013Co-Authors: Eric E Nilsson, Bin Zhang, Michael K SkinnerAbstract:Primordial Follicle assembly is the process by which ovarian Primordial Follicles are formed. During Follicle assembly oocyte nests break down and a layer of pre-granulosa cells surrounds individual oocytes to form Primordial Follicles. The pool of Primordial Follicles formed is the source of oocytes for ovulation during a female’s reproductive life. The current study utilized a systems approach to detect all genes that are differentially expressed in response to seven different growth factor and hormone treatments known to influence (increase or decrease) Primordial Follicle assembly in a neonatal rat ovary culture system. One novel factor, basic fibroblast growth factor (FGF2), was experimentally determined to inhibit Follicle assembly. The different growth factor and hormone treatments were all found to affect similar physiological pathways, but each treatment affected a unique set of differentially expressed genes (signature gene set). A gene bionetwork analysis identified gene modules of coordinately expressed interconnected genes and it was found that different gene modules appear to accomplish distinct tasks during Primordial Follicle assembly. Predictions of physiological pathways important to Follicle assembly were validated using ovary culture experiments in which ERK1/2 (MAPK1) activity was increased. A number of the highly interconnected genes in these gene networks have previously been linked to primary ovarian insufficiency (POI) and polycystic ovarian disease syndrome (PCOS). Observations have identified novel factors and gene networks that regulate Primordial Follicle assembly. This systems biology approach has helped elucidate the molecular control of Primordial Follicle assembly and provided potential therapeutic targets for the treatment of ovarian disease.
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inhibitory actions of anti mullerian hormone amh on ovarian Primordial Follicle assembly
PLOS ONE, 2011Co-Authors: Eric E Nilsson, Ryan Schindler, Marina I Savenkova, Michael K SkinnerAbstract:The current study was designed to investigate the actions of Anti-Mullerian Hormone (AMH) on Primordial Follicle assembly. Ovarian Primordial Follicles develop from the breakdown of oocyte nests during fetal development for the human and immediately after birth in rodents. AMH was found to inhibit Primordial Follicle assembly and decrease the initial Primordial Follicle pool size in a rat ovarian organ culture. The AMH expression was found to be primarily in the stromal tissue of the ovaries at this period of development, suggesting a stromal-epithelial cell interaction for Primordial Follicle assembly. AMH was found to promote alterations in the ovarian transcriptome during Primordial Follicle assembly with over 200 genes with altered expression. A gene network was identified suggesting a potential central role for the Fgf2/Nudt6 antisense transcript in the Follicle assembly process. A number of signal transduction pathways are regulated by AMH actions on the ovarian transcriptome, in particular the transforming growth factor – beta (TGFs) signaling process. AMH is the first hormone/protein shown to have an inhibitory action on Primordial Follicle assembly. Due to the critical role of the Primordial Follicle pool size for female reproduction, elucidation of factors, such as AMH, that regulate the assembly process will provide insights into potential therapeutics to manipulate the pool size and female reproduction.
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induction of ovarian Primordial Follicle assembly by connective tissue growth factor ctgf
PLOS ONE, 2010Co-Authors: Ryan Schindler, Eric E Nilsson, Michael K SkinnerAbstract:Primordial Follicle assembly is a process that occurs when oocyte nests break down to form individual Primordial Follicles. The size of this initial pool of Primordial Follicles in part determines the reproductive lifespan of the female. Connective tissue growth factor (CTGF) was identified as a potential regulatory candidate for this process in a previous microarray analysis of Follicle development. The current study examines the effects of CTGF and associated transforming growth factor beta 1 (TGFβ-1) on Follicle assembly. Ovaries were removed from newborn rat pups and placed in an organ culture system. The ovaries treated with CTGF for two days were found to have an increased proportion of assembled Follicles. CTGF was found to regulate the ovarian transcriptome during Primordial Follicle assembly and an integrative network of genes was identified. TGFβ-1 had no effect on Primordial Follicle assembly and in combination with CTGF decreased oocyte number in the ovary after two days of culture. Over ten days of treatment only the combined treatment of CTGF and TGFβ-1 was found to cause an increase in the proportion of assembled Follicles. Interestingly, treatment with TGFβ-1 alone resulted in fewer total oocytes in the ovary and decreased the Primordial Follicle pool size after ten days of culture. Observations indicate that CTGF alone or in combination with TGFβ-1 stimulates Primordial Follicle assembly and TGFβ-1 can decrease the Primordial Follicle pool size. These observations suggest the possibility of manipulating Primordial Follicle pool size and influencing female reproductive lifespan.
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gene bionetwork analysis of ovarian Primordial Follicle development
PLOS ONE, 2010Co-Authors: Eric E Nilsson, Bin Zhang, Ryan Schindler, Marina I Savenkova, Eric E Schadt, Michael K SkinnerAbstract:Ovarian Primordial Follicles are critical for female reproduction and comprise a finite pool of gametes arrested in development. A systems biology approach was used to identify regulatory gene networks essential for Primordial Follicle development. Transcriptional responses to eight different growth factors known to influence Primordial Follicles were used to construct a bionetwork of regulatory genes involved in rat Primordial Follicle development. Over 1,500 genes were found to be regulated by the various growth factors and a network analysis identified critical gene modules involved in a number of signaling pathways and cellular processes. A set of 55 genes was identified as potential critical regulators of these gene modules, and a sub-network associated with development was determined. Within the network two previously identified regulatory genes were confirmed (i.e., Pdgfa and Fgfr2) and a new factor was identified, connective tissue growth factor (CTGF). CTGF was tested in ovarian organ cultures and found to stimulate Primordial Follicle development. Therefore, the relevant gene network associated with Primordial Follicle development was validated and the critical genes and pathways involved in this process were identified. This is one of the first applications of network analysis to a normal developmental process. These observations provide insights into potential therapeutic targets for preventing ovarian disease and promoting female reproduction.
Melissa E Pepling - One of the best experts on this subject based on the ideXlab platform.
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arrest at the diplotene stage of meiotic prophase i is delayed by progesterone but is not required for Primordial Follicle formation in mice
Reproductive Biology and Endocrinology, 2016Co-Authors: Sudipta Dutta, Deion M Burks, Melissa E PeplingAbstract:Background In mammalian females, reproductive capacity is determined by the size of the Primordial Follicle pool. During embryogenesis, oogonia divide mitotically but cytokinesis is incomplete so oogonia remain connected in germ cell cysts. Oogonia begin to enter meiosis at 13.5 days postcoitum in the mouse and over several days, oocytes progress through the stages of meiotic prophase I arresting in the diplotene stage. Concurrently, germ cell cysts break apart and individual oocytes become surrounded by granulosa cells forming Primordial Follicles. In rats, inhibition of a synaptonemal complex protein caused premature arrival at the diplotene stage and premature Primordial Follicle assembly suggesting diplotene arrest might trigger Primordial Follicle formation. Cyst breakdown and Primordial Follicle formation are blocked by exposure to steroid hormones but hormone effects on the timing of diplotene arrest are unclear. Here, we asked: (1) if oocytes were required to arrest in diplotene before Follicles formed, (2) if all oocytes within a germ cell cyst arrested at diplotene synchronously, and (3) if steroid hormones affected progression through prophase I.
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the steroid hormone environment during Primordial Follicle formation in perinatal mouse ovaries
Biology of Reproduction, 2014Co-Authors: Sudipta Dutta, Connie J Markkappeler, Patricia B Hoyer, Melissa E PeplingAbstract:ABSTRACT Primordial Follicle assembly is essential for reproduction in mammalian females. Oocytes develop in germ cell cysts that in late fetal development begin break down into individual oocytes and become surrounded by pregranulosa cells, forming Primordial Follicles. As they separate, many oocytes are lost by apoptosis. Exposure to steroid hormones delays cyst breakdown, Follicle formation, and associated oocyte loss in some species. One model for regulation of Follicle formation is that steroid hormones in the maternal circulation keep cells in cysts and prevent oocyte death during fetal development but that late in pregnancy hormone levels drop, triggering cyst breakdown and associated oocyte loss. However, herein we found that, while maternal circulating levels of progesterone drop during late fetal development, maternal estradiol levels remain high. We hypothesized that fetal ovaries were the source of hormones and that late in fetal development their production stops. To test this, mRNA and prote...
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kit signaling regulates Primordial Follicle formation in the neonatal mouse ovary
Developmental Biology, 2013Co-Authors: Robin L Jones, Melissa E PeplingAbstract:Abstract The pool of Primordial Follicles determines the reproductive lifespan of the mammalian female, and its establishment is highly dependent upon proper oocyte cyst breakdown and regulation of germ cell numbers. The mechanisms controlling these processes remain a mystery. We hypothesized that KIT signaling might play a role in perinatal oocyte cyst breakdown, determination of oocyte numbers and the assembly of Primordial Follicles. We began by examining the expression of both KIT and KIT ligand in fetal and neonatal ovaries. KIT was expressed only in oocytes during cyst breakdown, but KIT ligand was present in both oocytes and somatic cells as Primordial Follicles formed. To test whether KIT signaling plays a role in cyst breakdown and Primordial Follicle formation, we used ovary organ culture to inhibit and activate KIT signaling during the time when these processes occur in the ovary. We found that when KIT was inhibited, there was a reduction in cyst breakdown and an increase in oocyte numbers. Subsequent studies using TUNEL analysis showed that when KIT was inhibited, cell death was reduced. Conversely, when KIT was activated, cyst breakdown was promoted and oocyte numbers decreased. Using Western blotting, we found increased levels of phosphorylated MAP Kinase when KIT ligand was added to culture. Taken together, these results demonstrate a role for KIT signaling in perinatal oocyte cyst breakdown that may be mediated by MAP Kinase downstream of KIT.
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estradiol progesterone and genistein inhibit oocyte nest breakdown and Primordial Follicle assembly in the neonatal mouse ovary in vitro and in vivo
Endocrinology, 2007Co-Authors: Ying Chen, Wendy N Jefferson, Retha R Newbold, Elizabeth Padillabanks, Melissa E PeplingAbstract:In developing mouse ovaries, oocytes develop as clusters of cells called nests or germ cell cysts. Shortly after birth, oocyte nests dissociate and granulosa cells surround individual oocytes forming Primordial Follicles. At the same time, two thirds of the oocytes die by apoptosis, but the link between oocyte nest breakdown and oocyte death is unclear. Although mechanisms controlling breakdown of nests into individual oocytes and selection of oocytes for survival are currently unknown, steroid hormones may play a role. Treatment of neonatal mice with natural or synthetic estrogens results in abnormal multiple oocyte Follicles in adult ovaries. Neonatal genistein treatment inhibits nest breakdown suggesting multiple oocyte Follicles are nests that did not break down. Here we investigated the role of estrogen signaling in nest breakdown and oocyte survival. We characterized an ovary organ culture system that recapitulates nest breakdown, reduction in oocyte number, Primordial Follicle assembly, and Follicle growth in vitro. We found that estradiol, progesterone, and genistein inhibit nest breakdown and Primordial Follicle assembly but have no effect on oocyte number both in organ culture and in vivo. Fetal ovaries, removed from their normal environment of high levels of pregnancy hormones, underwent premature nest breakdown and oocyte loss that was rescued by addition of estradiol or progesterone. Our results implicate hormone signaling in ovarian differentiation with decreased estrogen and progesterone at birth as the primary signaltoinitiateoocytenestbreakdownandFollicleassembly. These findings also provide insight into the mechanism of multiple oocyte Follicle formation. (Endocrinology 148: 3580–3590, 2007)
Eileen A Mclaughlin - One of the best experts on this subject based on the ideXlab platform.
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advances in human Primordial Follicle activation and premature ovarian insufficiency
Reproduction, 2020Co-Authors: Emmalee A Ford, Emma L Beckett, Shaun D Roman, Eileen A Mclaughlin, Jessie M SutherlandAbstract:: In women, the non-growing population of Follicles that comprise the ovarian reserve is determined at birth and serves as the reservoir for future fertility. This reserve of dormant, Primordial Follicles and the mechanisms controlling their selective activation which constitute the committing step into folliculogenesis are essential for determining fertility outcomes in women. Much of the available data on the mechanisms responsible for Primordial Follicle activation focuses on a selection of key molecular pathways, studied primarily in animal models, with findings often not synonymous in humans. The excessive induction of Primordial Follicle activation may cause the development of premature ovarian insufficiency (POI), a condition characterised by menopause before age 40 years. POI affects 1-2% of all women and is accompanied by additional health risks. Therefore, it is critical to further our understanding of Primordial Follicle activation in order to diagnose, treat and prevent premature infertility. Research in Primordial Follicle activation has focused on connecting new molecules to already established key signalling pathways, such as phosphatidylinositol 3-Kinase (PI3K) and mammalian target of rapamycin (mTOR). Additionally, other aspects of the ovarian environment, such as the function of the extracellular matrix, in contributing to Primordial Follicle activation have gained traction. Clinical applications are examining replication of this extracellular environment through the construction of biological matrices mimicking the 3D ovary, to support follicular growth through to ovulation. This review outlines the importance of the events leading to the establishment of the ovarian reserve and highlights the fundamental factors known to influence Primordial Follicle activation in humans presenting new horizons for female infertility treatment.
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staying alive pi3k pathway promotes Primordial Follicle activation and survival in response to 3mc induced ovotoxicity
Toxicological Sciences, 2012Co-Authors: Alexander P Sobinoff, Shaun D Roman, Brett Nixon, Eileen A MclaughlinAbstract:: 3-Methylcholanthrene (3MC) is a potent ovotoxicant capable of causing premature ovarian failure through Primordial Follicle depletion. Despite 3MCs ovotoxicity having been established for 30 years, relatively little information exists on the mechanisms. In this study, we examined the effects of 3MC exposure on the immature ovarian Follicle population. Microarray analysis revealed a complex mechanism of 3MC-induced ovotoxicity involving a number of cellular processes associated with xenobiotic metabolism, ovarian cancer, cell cycle progression, and cell death. 3MC exposure was also found to induce developing Follicle atresia and aberrant Primordial Follicle activation via the stimulation of PI3K/Akt and mammalian target of rapamycin (mTOR) signaling pathways. Inhibition of PI3K/Akt signaling resulted in the severe depletion of the Primordial Follicle pool, with further analysis identifying increased Akt1-stimulated Bad phosphoinhibition in 3MC-treated Primordial Follicles. Our results suggest that the Primordial Follicle pool enters a "prosurvival" state upon 3MC exposure and that its depletion is due to a vicious cycle of Primordial Follicle activation in an attempt to replace developing Follicles undergoing follicular atresia.
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jumping the gun smoking constituent bap causes premature Primordial Follicle activation and impairs oocyte fusibility through oxidative stress
Toxicology and Applied Pharmacology, 2012Co-Authors: Alexander P Sobinoff, Shaun D Roman, Brett Nixon, Eileen A MclaughlinAbstract:Benzo(a)pyrene (BaP) is an ovotoxic constituent of cigarette smoke associated with pre-mature ovarian failure and decreased rates of conception in IVF patients. Although the overall effect of BaP on female fertility has been documented, the exact molecular mechanisms behind its ovotoxicity remain elusive. In this study we examined the effects of BaP exposure on the ovarian transcriptome, and observed the effects of in vivo exposure on oocyte dysfunction. Microarray analysis of BaP cultured neonatal ovaries revealed a complex mechanism of ovotoxicity involving a small cohort of genes associated with follicular growth, cell cycle progression, and cell death. Histomorphological and immunohistochemical analysis supported these results, with BaP exposure causing increased Primordial Follicle activation and developing Follicle atresia in vitro and in vivo. Functional analysis of oocytes obtained from adult Swiss mice treated neonatally revealed significantly increased levels of mitochondrial ROS/lipid peroxidation, and severely reduced sperm-egg binding and fusion in both low (1.5 mg/kg/daily) and high (3 mg/kg/daily) dose treatments. Our results reveal a complex mechanism of BaP induced ovotoxicity involving developing Follicle atresia and accelerated Primordial Follicle activation, and suggest short term neonatal BaP exposure causes mitochondrial leakage resulting in reduced oolemma fluidity and impaired fertilisation in adulthood. This study highlights BaP as a key compound which may be partially responsible for the documented effects of cigarette smoke on follicular development and sub-fertility.
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suppressor of cytokine signaling 4 socs4 moderator of ovarian Primordial Follicle activation
Journal of Cellular Physiology, 2012Co-Authors: Jessie M Sutherland, Shaun D Roman, Brett Nixon, R Keightley, Rebecca L Robker, Darryl L Russell, Eileen A MclaughlinAbstract:Mammalian ovarian Primordial Follicle activation and regulation is considered as one of the most important stages of folliculogenesis and as such requires exquisite control. Selection of quiescent Follicles to enter the growing pool determines the rate of supply of maturing Follicles over the female reproductive lifespan. To coordinate this process a range of positive and negative input signals contribute to determine Follicle fate. This study demonstrates that the cytokine Leukemia Inhibitory Factor (LIF) activates the Janus Kinase 1/Signal Transducers and Activators of Transcription 3 (JAK1/STAT3) signaling pathway in pre-granulosa cells and positively regulates Primordial Follicle activation. Negative regulation of the JAK/STAT pathway is controlled by the suppressor of cytokine signaling 4 (SOCS4) protein, which target members of negative feedback loops, Cardiotrophin like Cytokine (CLC), Poly (rC) Binding Protein 1 (PCBP1), and Cytosolic Malate Dehydrogenase (MDH1) to suppress Follicle growth and development. J. Cell. Physiol. 227: 1188–1198, 2012. © 2011 Wiley Periodicals, Inc.
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understanding the villain dmba induced preantral ovotoxicity involves selective follicular destruction and Primordial Follicle activation through pi3k akt and mtor signaling
Toxicological Sciences, 2011Co-Authors: Alexander P Sobinoff, Shaun D Roman, Brett Nixon, Michelle Mahony, Eileen A MclaughlinAbstract:7,12-Dimethylbenz-[a]anthracene (DMBA) is an environmental carcinogen which has a potent ovotoxic affect on rat and mouse ovaries, causing complete follicular depletion resulting in premature ovarian failure. Although the overall effects of DMBA on ovarian folliculogenesis are well known, little is known about the exact molecular mechanisms behind its ovotoxicity. In this study, we characterized the mechanisms behind DMBA-induced ovotoxicity in immature Follicles. Microarray analysis of neonatal mouse ovaries exposed to DMBA in vitro revealed a multilayered mechanism of DMBA-induced neonatal ovotoxicity involving a distinct cohort of genes and ovarian signaling pathways primarily associated with follicular atresia, tumorigenesis, and follicular growth. Histomorphological and immunohistological analysis supported the microarray data, showing evidence of Primordial Follicle activation and preantral Follicle atresia both in vitro and in vivo. Further immunohistological analysis identified increased Akt1 phosphorylation, mTOR activation, and decreased FOXO3a expression in DMBA-treated Primordial oocytes. Our results reveal a novel mechanism of DMBA-induced preantral ovotoxicity involving selective immature Follicle destruction and Primordial Follicle activation involving downstream members of the PI3K/Akt and mTOR signaling pathways.
Wei Shen - One of the best experts on this subject based on the ideXlab platform.
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miR-378-3p maintains the size of mouse Primordial Follicle pool by regulating cell autophagy and apoptosis
Cell Death & Disease, 2020Co-Authors: Francesca Gioia Klinger, Massimo De Felici, Wei ShenAbstract:Abstract Primordial Follicle pool provides all available oocytes throughout the whole reproductive life span. Abnormal regulation in Primordial Follicle assembly leads to abnormal size of Primordial Follicle pool, even causes infertility. Here, miR-378-3p was proved to regulate mouse Primordial Follicle assembly both in vivo and in vitro. The expression of miR-378-3p significantly increased in mice ovaries from 17.5 dpc (days post coitum) up to 3 dpp (day post partum) compared with the expression of 16.5 dpc ovaries, which suggested that miR-378-3p was involved in Primordial Follicle assembly. To uncover the underlying mechanism, newborn mice ovaries were cultured in vitro in the presence of rapamycin and 3-methyladenine, which showed that the expression of miR-378-3p changed together with the percentage of Primordial Follicle. Moreover, during the normal process of Primordial Follicle assembly between 17.6 dpc and 3 dpp, autophagy is activated, while, apoptosis is inhibited. The in vivo results showed that newborn mice starved for 1.5 days showing the increased miR-378-3p, activated autophagy and inhibited apoptosis in the ovaries, had more percentage of Primordial Follicles. Over-expression of miR-378-3p using miR-378-3p agomir caused increased percentage of Primordial Follicle, increased level of autophagy, and decreased level of apoptosis. Knockdown of miR-378-3p by miR-378-3p antiagomir had the opposite results. Using pmirGLO Dual-Luciferase miRNA Target Expression system, we confirmed both PDK1 and Caspase9 were targets of miR-378-3p, which suggested that miR-378-3p activated autophagy by targeting PDK1 and inhibited apoptosis by targeting Caspase9. MiR-378-3p could be used as a biomarker of diseases caused by abnormal size of Primordial Follicle pool for diagnosis, prevention, or therapy.
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The role of autophagy during murine Primordial Follicle assembly.
Aging, 2018Co-Authors: Yong-yong Wang, Wei Shen, Shun-feng Cheng, Lan Li, Yong Zhao, Hong ChenAbstract:: It is generally accepted that significant germ cell loss occurs during the establishment of the Primordial Follicle pool in most mammalian ovaries around the time of birth. However, the underlying mechanisms responsible for these processes remain largely unknown. In this investigation, we explored the role of autophagy during the establishment of the Primordial Follicle pool and found that autophagy was active in this process. Our data suggested that 17.5 dpc ovaries treated with rapamycin displayed a delay in germ cell cyst breakdown resulting in more oocytes at day 5 of treatment, while, ovaries that treated with 3-MA showed the opposite effect. We found that rapamycin treatment promoted autophagy and depressed cell apoptosis increasing the number of NOBOX positive oocytes. Furthermore, our results also revealed that epigenetic regulator, Sirt1, plays a role in germ cell loss. An epigenetic inhibitor or RNAi treatment of Sirt1, showed an increased level of H4K16ac and a decreased level of autophagy. Thus, these data indicate that autophagy prevents germ cell over loss during the establishment of Primordial Follicle pool, and this process may be influenced by Sirt1-invovled epigenetic regulation.
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Low expression of SEMA6C accelerates the Primordial Follicle activation in the neonatal mouse ovary.
Journal of Cellular and Molecular Medicine, 2017Co-Authors: Su Zhou, Wei Shen, Jing Cheng, Yueyue Xi, Suzhen Yuan, Fangfang Fu, Ting Ding, Shixuan WangAbstract:: The Primordial Follicle assembly, activation and the subsequent development are critical processes for female reproduction. A limited number of Primordial Follicles are activated to enter the growing Follicle pool each wave, and the Primordial Follicle pool progressively diminishes over a woman's life-time. The number of remaining Primordial Follicles represents the ovarian reserve. Identification and functional investigation of the factors involved in follicular initial recruitment will be of great significance to the understanding of the female reproduction process and ovarian ageing. In this study, we aimed to study whether and how semaphorin 6C (Sema6c) regulated the Primordial Follicle activation in the neonatal mouse ovary. The attenuation of SEMA6C expression by SiRNA accelerated the Primordial Follicle activation in the in vitro ovary culture system. PI3K-AKT-rpS6 pathway was activated when SEMA6C expression was down-regulated. And the LY294002 could reverse the effect of low SEMA6C expression on Primordial Follicle activation. Our findings revealed that Sema6c was involved in the activation of Primordial Follicles, and the down-regulation of SEMA6C led to massive Primordial Follicle activation by interacting with the PI3K-AKT-rpS6 pathway, which might also provide valuable information for understanding premature ovarian failure and ovarian ageing.
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zearalenone exposure impairs ovarian Primordial Follicle formation via down regulation of lhx8 expression in vitro
Toxicology and Applied Pharmacology, 2017Co-Authors: Guoliang Zhang, Wei Shen, Yapeng Li, Yanzhong Feng, Bo Li, Fan Yang, C M Nyachoti, Lan LiAbstract:Abstract Zearalenone (ZEA) is an estrogenic mycotoxin mainly produced as a secondary metabolite by numerous species of Fusarium. Previous work showed that ZEA had a negative impact on domestic animals with regard to reproduction. The adverse effects and the mechanisms of ZEA on mammalian ovarian folliculogenesis remain largely unknown, particularly its effect on Primordial Follicle formation. Thus, we investigated the biological effects of ZEA exposure on murine ovarian germ cell cyst breakdown and Primordial Follicle assembly. Our results demonstrated that newborn mouse ovaries exposed to 10 or 30 μM ZEA in vitro had significantly less germ cell numbers compared to the control group. Moreover, the presence of ZEA in vitro increased the numbers of TUNEL and γH2AX positive cells within mouse ovaries and the ratio of mRNA levels of the apoptotic genes Bax/Bcl-2 . Furthermore, ZEA exposure reduced the mRNA of oocyte specific genes such as LIM homeobox 8 ( Lhx8 ), newborn ovary homeobox ( Nobox ), spermatogenesis and oogenesis helix-loop-helix ( Sohlh2 ), and factor in the germline alpha ( Figlα ) in a dose dependent manner. Exposure to ZEA led to remarkable changes in the Lhx8 3′-UTR DNA methylation dynamics in oocytes and severely impaired folliculogenesis in ovaries after transplantation under the kidney capsules of immunodeficient mice. In conclusion, ZEA exposure impairs mouse Primordial Follicle formation in vitro .
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di 2 ethylhexyl phthalate and bisphenol a exposure impairs mouse Primordial Follicle assembly in vitro
Environmental and Molecular Mutagenesis, 2014Co-Authors: Teng Zhang, Lan Li, Hong Chen, Massimo De Felici, Xifeng Zhang, Yang Zhou, Linqing Wang, Wei ShenAbstract:Bisphenol-A (BPA) and diethylhexyl phthalate (DEHP) are estrogenic compounds widely used in commercial plastic products. Previous studies have shown that exposure to such compounds have adverse effects on various aspects of mammalian reproduction including folliculogenesis. The objective of this study was to examine the effects of BPA and DEHP exposure on Primordial Follicle formation. We found that germ cell nest breakdown and Primordial Follicle assembly were significantly reduced when newborn mouse ovaries were exposed to 10 or 100 μM BPA and DEHP in vitro. Moreover, BPA and DEHP exposure increased the number of TUNEL positive oocytes and the mRNA level of the pro-apoptotic gene Bax in oocytes. These effects were associated with decreased expression of oocyte specific genes such as LIM homeobox 8 (Lhx8), factor in the germline alpha (Figla), spermatogenesis and oogenesis helix-loop-helix (Sohlh2), and newborn ovary homeobox (Nobox). Interestingly, BPA and DEHP exposure also prevented DNA demethylation of CpG sites of the Lhx8 gene in oocytes, a process normally associated with folliculogenesis. Finally, folliculogenesis was severely impaired in BPA and DEHP exposed ovaries after transplantation into the kidney capsules of immunodeficient mice. In conclusion, BPA and DEHP exposures impair mouse Primordial Follicle assembly in vitro.