scholarly journals A novel marsupial pri-miRNA transcript has a putative role in gamete maintenance and defines a vertebrate miRNA cluster paralogous to the miR-15a/miR-16-1 cluster

Reproduction ◽  
2011 ◽  
Vol 142 (4) ◽  
pp. 539-550 ◽  
Author(s):  
Phil Chi Khang Au ◽  
Stephen Frankenberg ◽  
Lynne Selwood ◽  
Mary Familari
Keyword(s):  
Molecular Mechanisms ◽  
Primordial Germ Cells ◽  
Primordial Follicle ◽  
Bioinformatic Analysis ◽  
Male Reproduction ◽  
Follicle Cells ◽  
Mirna Cluster ◽  
Supporting Cells ◽  
Primordial Follicles ◽  
Wide Range

Successful maintenance, survival and maturation of gametes rely on bidirectional communication between the gamete and its supporting cells. Before puberty, factors from the gamete and its supporting cells are necessary for spermatogonial stem cell and primordial follicle oocyte maintenance. Following gametogenesis, gametes rely on factors and nutrients secreted by cells of the reproductive tracts, the epididymis and/or oviduct, to complete maturation. Despite extensive studies on female and male reproduction, many of the molecular mechanisms of germ cell maintenance remain relatively unknown, particularly in marsupial species. We present the first study and characterisation of a novel primary miRNA transcript, pri-miR-16c, in the marsupial, the stripe-faced dunnart. Bioinformatic analysis showed that its predicted processed miRNA – miR-16c – is present in a wide range of vertebrates, but not eutherians. In situ hybridisation revealed dunnart pri-miR-16c expression in day 4 (primordial germ cells) and day 7 (oogonia) pouch young, in primary oocytes and follicle cells of primordial follicles but then only in follicle cells of primary, secondary and antral follicles in adult ovaries. In the adult testis, pri-miR-16c transcripts were present in the cytoplasm of spermatogonial cells. The oviduct and the epididymis both showed expression, but not any other somatic tissues examined or conceptuses during early embryonic development. This pattern of expression suggests that pri-miR-16c function may be associated with gamete maintenance, possibly through mechanisms involving RNA transfer, until the zygote enters the uterus at the pronuclear stage.

scholarly journals Follicular assembly: mechanisms of action

Reproduction ◽  
2012 ◽  
Vol 143 (2) ◽  
pp. 139-149 ◽  
Author(s):  
Melissa E Pepling
Keyword(s):  
Cell Death ◽  
Germ Line ◽  
Primordial Germ Cells ◽  
Primordial Follicle ◽  
Mechanisms Of Action ◽  
Initial Number ◽  
Primordial Follicles ◽  
Meiotic Progression ◽  
Germ Cell Cysts ◽  
Reproductive Cancers

The differentiation of primordial germ cells (PGCs) into functional oocytes is important for the continuation of species. In mammals, PGCs begin to differentiate into oocytes during embryonic development. Oocytes develop in clusters called germ line cysts. During fetal or neonatal development, germ cell cysts break apart into single oocytes that become surrounded by pregranulosa cells to form primordial follicles. During the process of cyst breakdown, a subset of cells in each cyst undergoes cell death with only one-third of the initial number of oocytes surviving to form primordial follicles. The mechanisms that control cyst breakdown, oocyte survival, and follicle assembly are currently under investigation. This review describes the mechanisms that have been implicated in the control of primordial follicle formation, which include programmed cell death regulation, growth factor and other signaling pathways, regulation by transcription factors and hormones, meiotic progression, and changes in cell adhesion. Elucidation of mechanisms leading to formation of the primordial follicle pool will help research efforts in ovarian biology and improve treatments of female infertility, premature ovarian failure, and reproductive cancers.

scholarly journals Signaling Pathways in Cervical Cancer Chemoresistance: Are microRNAs and Long-Noncoding RNAs the Main Culprits?

2020 ◽  
Author(s):  
Seyyed Reza Mousavi ◽  
Nima Hemmat ◽  
Hossein Bannazadeh Baghi ◽  
Afshin Derakhshani ◽  
Stefania Tommasi ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Drug Resistance ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Bioinformatic Analysis ◽  
Aberrant Expression ◽  
Recurrent Cervical Cancer ◽  
Response To Chemotherapy ◽  
Wide Range ◽  
Non Coding Rnas

Cervical cancer is known as one of the most important cancers in women worldwide. Chemotherapy is a standard treatment for advanced/recurrent cervical cancer in which the prognosis of the disease is really poor and the 1-year survival chance in these patients is maximally 20%. However, resistance to anticancer drugs is a major problem in treating cancer. Cervical cancer stem cells are considered as a fundamental cause of chemo and radio-resistance and also relapse after primary successful treatment. Signaling pathways include a wide range of molecular mechanisms contribute to drug resistance. Recently, microRNAs (miRNAs) are announced as a group of molecular biomarkers involving in response to chemotherapy in cancer patients. As the miRNAs, there are some long non-coding RNAs (LncRNAs) which their aberrant expression is considered as a biomarker for monitoring chemoresistance. In this review, we summarized current reports about the involvement of signaling pathways during chemoresistance in cervical cancer. Then, genes that have been demonstrated their involvement during drug resistance in cervical cancer were tabulated. Further, miRNAs that have been reported as biomarkers during treatment are listed. By bioinformatic analysis, we predictedmiR-335-5p and miR-16-5p as the most potential biomarkers for monitoring resistance to chemotherapy. Finally, long non-coding RNAs that have been introduced in recent studies as novel biomarkers during the response to chemotherapy were mentioned.

scholarly journals Hearing Loss in Neurological Disorders

2021 ◽  
Vol 9 ◽  
Author(s):  
Siyu Li ◽  
Cheng Cheng ◽  
Ling Lu ◽  
Xiaofeng Ma ◽  
Xiaoli Zhang ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cells ◽  
Neurological Disorders ◽  
Molecular Mechanisms ◽  
Relevant Literature ◽  
Autism Spectrum ◽  
Supporting Cells ◽  
Cochlear Hair Cells ◽  
Wide Range ◽  
Histological Characteristics

Sensorineural hearing loss (SNHL) affects approximately 466 million people worldwide, which is projected to reach 900 million by 2050. Its histological characteristics are lesions in cochlear hair cells, supporting cells, and auditory nerve endings. Neurological disorders cover a wide range of diseases affecting the nervous system, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), autism spectrum disorder (ASD), etc. Many studies have revealed that neurological disorders manifest with hearing loss, in addition to typical nervous symptoms. The prevalence, manifestations, and neuropathological mechanisms underlying vary among different diseases. In this review, we discuss the relevant literature, from clinical trials to research mice models, to provide an overview of auditory dysfunctions in the most common neurological disorders, particularly those associated with hearing loss, and to explain their underlying pathological and molecular mechanisms.

scholarly journals Mammalian foetal ovarian development: consequences for health and disease

Reproduction ◽  
2012 ◽  
Vol 143 (2) ◽  
pp. 151-163 ◽  
Author(s):  
Mai A Sarraj ◽  
Ann E Drummond
Keyword(s):  
Molecular Mechanisms ◽  
Ovarian Development ◽  
Primordial Germ Cells ◽  
Adult Life ◽  
Primordial Follicles ◽  
Cellular Processes ◽  
Foetal Life ◽  
Health And Disease ◽  
Female Specific ◽  
Bipotential Gonad

The development of a normal ovary during foetal life is essential for the production and ovulation of a high-quality oocyte in adult life. Early in embryogenesis, the primordial germ cells (PGCs) migrate to and colonise the genital ridges. Once the PGCs reach the bipotential gonad, the absence of the sex-determining region on the Y chromosome (SRY) gene and the presence of female-specific genes ensure that the indifferent gonad takes the female pathway and an ovary forms. PGCs enter into meiosis, transform into oogonia and ultimately give rise to oocytes that are later surrounded by granulosa cells to form primordial follicles. Various genes and signals are implicated in germ and somatic cell development, leading to successful follicle formation and normal ovarian development. This review focuses on the differentiation events, cellular processes and molecular mechanisms essential for foetal ovarian development in the mice and humans. A better understanding of these early cellular and morphological events will facilitate further study into the regulation of oocyte development, manifestation of ovarian disease and basis of female infertility.

Cisplatin- and cyclophosphamide-induced primordial follicle depletion is caused by direct damage to oocytes

2019 ◽  
Vol 25 (8) ◽  
pp. 433-444 ◽  
Author(s):  
Q N Nguyen ◽  
N Zerafa ◽  
S H Liew ◽  
J K Findlay ◽  
M Hickey ◽  
...  
Keyword(s):  
Ovarian Reserve ◽  
Molecular Mechanisms ◽  
Ovarian Function ◽  
Primordial Follicle ◽  
Cell Types ◽  
Tunel Staining ◽  
Specific Cell ◽  
Primordial Follicles ◽  
Cellular Targets ◽  
Direct Damage

Abstract It is well established that DNA-damaging chemotherapies can cause infertility and ovarian endocrine failure by depleting the ovarian reserve of primordial follicles. Currently, no effective pharmacological therapies exist for the preservation of long-term fertility and ovarian function in female cancer patients, due to a limited understanding of the mechanisms of chemotherapy-induced follicle depletion. This study investigated the cellular targets, molecular mechanisms, and temporal course of ovarian reserve depletion following treatment with commonly used chemotherapeutic drugs. Adult female C57BL/6 mice were injected i.p. with saline, cisplatin (5mg/kg), or cyclophosphamide (300mg/kg); ovaries were harvested after 8 or 24 hours. Follicle counts showed depletion of all follicular stages 24 hours after administration of cisplatin or cyclophosphamide. Eight hours post-treatment, H2A histone family member X (γH2AX) immunofluorescence showed DNA double-stranded breaks at all follicular stages, including within primordial follicle oocytes. This staining was resolving by 24 hours, indicating that primordial follicle oocytes begin to undergo either apoptosis or repair in this timeframe. γH2AX-positive follicles were further examined to identify the specific cell types damaged. In primordial, transitional, and primary follicles, only oocytes sustained DNA damage, whereas in secondary and antral follicles, only somatic cells were affected. TUNEL staining confirmed that apoptosis occurs in these targeted cell types. Whilst multi-drug and multi-dose regimens were not examined, this study conclusively shows that cyclophosphamide and cisplatin cause direct damage to primordial follicle oocytes, which then undergo apoptosis. Therefore, future pharmacological strategies to prevent chemotherapy-induced infertility in females must specifically prevent primordial follicle oocyte death.

scholarly journals Actions of anti-Müllerian hormone on the ovarian transcriptome to inhibit primordial to primary follicle transition

Reproduction ◽  
2007 ◽  
Vol 134 (2) ◽  
pp. 209-221 ◽  
Author(s):  
Eric Nilsson ◽  
Natalie Rogers ◽  
Michael K Skinner
Keyword(s):  
Growth Factor ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Keratinocyte Growth Factor ◽  
Primordial Follicle ◽  
Follicle Development ◽  
Primary Follicle ◽  
Molecular Control ◽  
Primordial Follicles ◽  
Cellular Pathways

The oocytes found within the primordial follicles of mammalian ovaries remain quiescent for months to years until they receive the appropriate signals to undergo the primordial to primary follicle transition and initiate folliculogenesis. The molecular mechanisms and extracellular signaling factors that regulate this process remain to be fully elucidated. The current study investigates the mechanisms utilized by anti-Müllerian hormone (AMH; i.e. Müllerian inhibitory substance) to inhibit the primordial to primary follicle transition. Ovaries from 4-day-old rats were placed into organ culture and incubated in the absence or presence of AMH, either alone or in combination with known stimulators of follicle transition, including basic fibroblast growth factor (bFGF), kit ligand (KITL), or keratinocyte growth factor (KGF). Following 10 days of culture, the ovaries were sectioned, stained, and morphologically evaluated to determine the percentage of primordial versus developing follicles. As previously demonstrated, AMH treatment decreased primordial to primary follicle transition. Interestingly, AMH inhibited the stimulatory actions of KITL, bFGF, and KGF. Therefore, AMH can inhibit the basal and stimulated development of primordial follicles. To investigate the mechanism of AMH actions, the influence AMH has on the ovarian transcriptome was analyzed. AMH treatment when compared with controls was found to alter the expression of 707 genes. The overall effect of AMH exposure is to decrease the expression of stimulatory factors, increase the expression of inhibitory factors, and regulate cellular pathways (e.g. transforming growth factor β signaling pathway) that result in the inhibition of primordial follicle development. Analysis of the regulatory factors and cellular pathways altered by AMH provides a better understanding of the molecular control of primordial follicle development.

scholarly journals Oocyte Survival and Development During Follicle Formation and Folliculogenesis in Mice Lacking Aromatase

2021 ◽  
Author(s):  
Jessica M. Toothaker ◽  
Kristen Roosa ◽  
Alexandra Voss ◽  
Suzanne M. Getman ◽  
Melissa Pepling
Keyword(s):  
Germ Cells ◽  
Ovarian Reserve ◽  
Primordial Germ Cells ◽  
Primordial Follicle ◽  
Follicle Development ◽  
Primordial Follicles ◽  
Survival And Development ◽  
Hemosiderin Deposits

Abstract BackgroundAssembly of oocytes into primordial follicles is essential for establishing the ovarian reserve required for female fertility. In mice, this process begins during embryonic development. Primordial germ cells form cysts by incomplete mitosis until 13.5 days post coitum (dpc). These cysts break down just before birth. Some oocytes undergo apoptosis while surviving oocytes are enclosed by granulosa cells to form primordial follicles. Cyst breakdown and primordial follicle formation were previously shown to be inhibited by estradiol and estrogenic compounds in vitro, suggesting that estrogen is important for regulation of this process. MethodsTo determine the role of fetal estrogen in cyst breakdown and follicle formation these processes were quantified in aromatase deficient (ArKO) mice between 17.5 dpc and postnatal day (PND) 9. Ovaries of ArKO mice were also examined at 2-week intervals to determine if folliculogenesis is affected by lack of estrogen and the age at which the typical ArKO ovarian phenotype first appears. ResultsOocyte number, follicle assembly and follicle development in ArKO mice did not differ from controls between 17.5 dpc and PND9 except for a difference in the proportion of follicles at the primordial and primary stage at PND7. At 2 weeks, ArKO heterozygous and homozygous ovaries still had oocytes in cyst while all oocytes were enclosed in follicles in wildtype ovaries. From 2 to 8 weeks oocyte numbers were similar in all genotypes though there was a trend toward fewer total oocytes in ArKO homozygous females as compared to controls at 8 weeks and a significant reduction at 10 weeks. Abnormal structures such as hemorrhagic follicles and hemosiderin deposits were also observed starting at 6 weeks. ConclusionsThese results suggest that a lack of fetal estrogen does not affect the rate of cyst breakdown or primordial follicle formation perinatally, and maternal estrogen or other signals are the chief regulators. Furthermore, the typical ArKO ovarian phenotype occurs earlier than previously reported.

scholarly journals CHEK2 SIGNALING IS THE KEY REGULATOR OF OOCYTE SURVIVAL AFTER CHEMOTHERAPY

2021 ◽  
Author(s):  
Chihiro Emori ◽  
Zachary Boucher ◽  
Ewelina Bolcun-Filas
Keyword(s):  
Ovarian Function ◽  
Kinase Inhibitor ◽  
Critical Role ◽  
Treatment Strategies ◽  
Primordial Follicle ◽  
Checkpoint Kinase ◽  
Primordial Follicles ◽  
Chemotherapy Drugs ◽  
Response To Chemotherapy ◽  
Wide Range

Radiation and chemotherapy can damage the primordial follicle reserve in female cancer patients leading to ovarian failure and infertility. Preservation of ovarian function requires treatment strategies that prevent loss of immature oocytes in primordial follicles during cancer therapy. Checkpoint kinase 2 (CHEK2) inhibition prevents loss of primordial oocytes caused by DNA damage and thus is a promising target for ovoprotective treatment against genotoxic agents. To determine which cancer treatments could benefit from ovoprotective activity of CHEK2 inhibition we investigated oocyte survival in Chek2-/- mice exposed to different chemotherapy drugs. Here, we show that loss of CHEK2 function prevents elimination of primordial oocytes damaged by cisplatin, cyclophosphamide, mafosfamide, doxorubicin, and etoposide, suggesting it could be used to reduce ovarian damage caused by wide range of drugs. Using genetic knockouts we reveal a critical role for TRP53 in oocyte response to chemotherapy drugs and show that both targets of CHEK2, TAp63 and TRP53, are activated by cisplatin and cyclophosphamide. Furthermore, we show that checkpoint kinase inhibitor and radiation- and chemotherapy sensitizer AZD7762 reduces oocyte elimination after radiation and chemotherapy treatments, despite its cytotoxic effect on ovarian somatic cells. Altogether, these findings demonstrate the role for CHEK2 as the master regulator of primordial oocyte survival or death and credential its targeting for ovoprotective treatments.

scholarly journals Molecular analysis of the effects of steroid hormones on mouse meiotic prophase I progression

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Deion M. Burks ◽  
Margaret R. McCoy ◽  
Sudipta Dutta ◽  
Connie J. Mark-Kappeler ◽  
Patricia B. Hoyer ◽  
...  
Keyword(s):  
Organ Culture ◽  
Granulosa Cells ◽  
Meiotic Prophase ◽  
Primordial Germ Cells ◽  
Primordial Follicle ◽  
Pachytene Stage ◽  
Primordial Follicles ◽  
Diplotene Stage ◽  
Prophase I ◽  
Meiotic Prophase I

Abstract Background Infertility is linked to depletion of the primordial follicle pool consisting of individual oocytes arrested at the diplotene stage of meiotic prophase I surrounded by granulosa cells. Primordial germ cells, the oocyte precursors, begin to differentiate during embryonic development. These cells migrate to the genital ridge and begin mitotic divisions, remaining connected, through incomplete cytokinesis, in clusters of synchronously dividing oogonia known as germ cell cysts. Subsequently, they enter meiosis, become oocytes and progress through prophase I to the diplotene stage. The cysts break apart, allowing individual oocytes to be surrounded by a layer of granulosa cells, forming primordial follicles each containing a diplotene arrested oocyte. A large number of oocytes are lost coincident with cyst breakdown, and may be important for quality control of primordial follicle formation. Exposure of developing ovaries to exogenous hormones can disrupt cyst breakdown and follicle formation, but it is unclear if hormones affect progression of oocytes through prophase I of meiosis. Methods Fetal ovaries were treated in organ culture with estradiol, progesterone, or both hormones, labeled for MSY2 or Synaptonemal complex protein 3 (SYCP3) using whole mount immunocytochemistry and examined by confocal microscopy. Meiotic prophase I progression was also followed using the meiotic surface spread technique. Results MSY2 expression in oocytes was reduced by progesterone but not estradiol or the hormone combination. However, while MSY2 expression was upregulated during development it was not a precise marker for the diplotene stage. We also followed meiotic prophase I progression using antibodies against SYCP3 using two different methods, and found that the percent of oocytes at the pachytene stage peaked at postnatal day 1. Finally, estradiol and progesterone treatment together but not either alone in organ culture increased the percent of oocytes at the pachytene stage. Conclusions We set out to examine the effects of hormones on prophase I progression and found that while MSY2 expression was reduced by progesterone, MSY2 was not a precise diplotene stage marker. Using antibodies against SYCP3 to identify pachytene stage oocytes we found that progesterone and estradiol together delayed progression of oocytes through prophase I.

scholarly journals Very Small Embryonic-Like Stem Cells: Implications in Reproductive Biology

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Deepa Bhartiya ◽  
Sreepoorna Unni ◽  
Seema Parte ◽  
Sandhya Anand
Keyword(s):  
Stem Cells ◽  
Germ Cells ◽  
Asymmetric Cell Division ◽  
Functional Unit ◽  
Primordial Germ Cells ◽  
Primordial Follicle ◽  
Human Reproduction ◽  
Primordial Follicles ◽  
Epiblast Stem Cells ◽  
Reproductive Processes

The most primitive germ cells in adult mammalian testis are the spermatogonial stem cells (SSCs) whereas primordial follicles (PFs) are considered the fundamental functional unit in ovary. However, this central dogma has recently been modified with the identification of a novel population of very small embryonic-like stem cells (VSELs) in the adult mammalian gonads. These stem cells are more primitive to SSCs and are also implicated during postnatal ovarian neo-oogenesis and primordial follicle assembly. VSELs are pluripotent in nature and characterized by nuclear Oct-4A, cell surface SSEA-4, and other pluripotent markers like Nanog, Sox2, and TERT. VSELs are considered to be the descendants of epiblast stem cells and possibly the primordial germ cells that persist into adulthood and undergo asymmetric cell division to replenish the gonadal germ cells throughout life. Elucidation of their role during infertility, endometrial repair, superovulation, and pathogenesis of various reproductive diseases like PCOS, endometriosis, cancer, and so on needs to be addressed. Hence, a detailed review of current understanding of VSEL biology is pertinent, which will hopefully open up new avenues for research to better understand various reproductive processes and cancers. It will also be relevant for future regenerative medicine, translational research, and clinical applications in human reproduction.

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