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 Specificity of the requirement for Foxo3 in primordial follicle activation

Reproduction ◽  
2007 ◽  
Vol 133 (5) ◽  
pp. 855-863 ◽  
Author(s):  
George B John ◽  
Lane J Shirley ◽  
Teresa D Gallardo ◽  
Diego H Castrillon
Keyword(s):  
Germ Line ◽  
Primordial Follicle ◽  
Forkhead Transcription Factor ◽  
Primordial Follicles ◽  
Mouse Mutants ◽  
Physiological Processes ◽  
Primordial Follicle Activation ◽  
Mammalian Female ◽  
Structure Assembly ◽  
Follicle Activation

Primordial follicles are long-lived structures assembled early in life. The mechanisms that control the balance between the conservation and the activation of primordial follicles are critically important for fertility and dictate the onset of menopause. The forkhead transcription factor Foxo3 serves an essential role in these processes by suppressing the growth of primordial follicles, thereby preserving them until later in life. While other factors regulating primordial follicle growth have been described, most serve multiple functions at several stages of female germ cell or follicle development, and corresponding mouse mutants exhibit pleiotropic phenotypes with disruption of multiple stages of follicle assembly, development, or survival. To investigate the possibility that Foxo3 also functions in other aspects of ovarian development beyond its known role in primordial follicle activation (PFA), we performed detailed analyses of mouse ovaries including electron microscopy to study primordial follicle structure, assembly, and early growth. These analyses revealed that the timing of primordial follicle assembly, early oocyte survival, and the expression of early germ line markers were unaffected in early Foxo3 ovaries. Taken together, these studies demonstrate that the phenotype associated with Foxo3 deficiency is remarkably specific for PFA and further support the placement of Foxo3 in a unique phenotypic class among mammalian female sterile mutants. Lastly, we discuss the implications of the specificity of this mutant phenotype with regard to the hypothesis that oocyte regeneration may occur in adults and serves as a means to replenish oocytes lost via natural physiological processes.

scholarly journals XY oocytes of sex-reversed females with a Sry mutation deviate from the normal developmental process beyond the mitotic stage†

2018 ◽  
Vol 100 (3) ◽  
pp. 697-710 ◽  
Author(s):  
Akihiko Sakashita ◽  
Takuya Wakai ◽  
Yukiko Kawabata ◽  
Chiaki Nishimura ◽  
Yusuke Sotomaru ◽  
...  
Keyword(s):  
Germ Cells ◽  
Developmental Process ◽  
Sex Differentiation ◽  
Primordial Germ Cells ◽  
Primordial Follicle ◽  
Genetic Ablation ◽  
Female Mice ◽  
Meiotic Progression ◽  
Molecular Etiology ◽  
Mitotic Proliferation

Abstract The fertility of sex-reversed XY female mice is severely impaired by a massive loss of oocytes and failure of meiotic progression. This phenomenon remains an outstanding mystery. We sought to determine the molecular etiology of XY oocyte dysfunction by generating sex-reversed females that bear genetic ablation of Sry, a vital sex determination gene, on an inbred C57BL/6 background. These mutant mice, termed XYsry− mutants, showed severe attrition of germ cells during fetal development, resulting in the depletion of ovarian germ cells prior to sexual maturation. Comprehensive transcriptome analyses of primordial germ cells (PGCs) and postnatal oocytes demonstrated that XYsry− females had deviated significantly from normal developmental processes during the stages of mitotic proliferation. The impaired proliferation of XYsry− PGCs was associated with aberrant β-catenin signaling and the excessive expression of transposable elements. Upon entry to the meiotic stage, XYsry− oocytes demonstrated extensive defects, including the impairment of crossover formation, the failure of primordial follicle maintenance, and no capacity for embryo development. Together, these results suggest potential molecular causes for germ cell disruption in sex-reversed female mice, thereby providing insights into disorders of sex differentiation in humans, such as “Swyer syndrome,” in which patients with an XY karyotype present as typical females and are infertile.

Transgenerational inheritance of ovarian development deficiency induced by maternal diethylhexyl phthalate exposure

2015 ◽  
Vol 27 (8) ◽  
pp. 1213 ◽  
Author(s):  
Xi-Feng Zhang ◽  
Teng Zhang ◽  
Zhe Han ◽  
Jing-Cai Liu ◽  
Yu-Ping Liu ◽  
...  
Keyword(s):  
Ovarian Development ◽  
Primordial Follicle ◽  
Abnormal Development ◽  
Endogenous Hormones ◽  
Transgenerational Inheritance ◽  
Primordial Follicles ◽  
Diethylhexyl Phthalate ◽  
Meiotic Progression ◽  
Pregnant Mice ◽  
Dehp Exposure

Diethylhexyl phthalate (DEHP) is a widely used industrial additive for increasing plastic flexibility. It disrupts the physiological functions of endogenous hormones and induces abnormal development of mammals. The objectives of the present study were to evaluate the effects of DEHP exposure on ovarian development of pregnant mice and whether the effects are inheritable. We found that the synthesis of oestradiol in pregnant mice after DEHP exposure was significantly decreased, and that the first meiotic progression of female fetal germ cells was delayed. Furthermore, the DNA methylation level of Stra8 was increased and the expression levels of Stra8 were significantly decreased. An accelerated rate of follicle recruitment in F1 mice was responsible for the depletion of the primordial-follicle pool. Maternal DEHP exposure also significantly accelerated the recruitment of primordial follicles in F2 mice. In conclusion, our results indicated that maternal DEHP exposure induced ovarian development deficiency, which was transgenerational in mice.

scholarly journals The primordial follicle reserve is not renewed after chemical or γ-irradiation mediated depletion

Reproduction ◽  
2012 ◽  
Vol 143 (4) ◽  
pp. 469-476 ◽  
Author(s):  
J B Kerr ◽  
L Brogan ◽  
M Myers ◽  
K J Hutt ◽  
T Mladenovska ◽  
...  
Keyword(s):  
Stem Cells ◽  
Germ Line ◽  
Trichostatin A ◽  
Primordial Follicle ◽  
Whole Body ◽  
Postnatal Life ◽  
Γ Irradiation ◽  
Primordial Follicles ◽  
Adult Mice ◽  
Complete Ablation

Reports indicate that germ-line stem cells present in adult mice can rapidly generate new oocytes and contribute to the primordial follicle reserve following conditions of ovotoxic stress. We further investigated the hypothesis that adult mice have the capacity to generate new oocytes by monitoring primordial follicle numbers throughout postnatal life and following depletion of the primordial follicle reserve by exposure to doxorubicin (DXR), trichostatin A (TSA), or whole-body γ-irradiation. We show that primordial follicle number remains stable in adult C57BL/6 mice between the ages of 25 and 100 days. However, within 2 days of treatment with DXR or TSA, primordial follicle numbers had declined to 65 and 51% respectively (P<0.05–0.01 when compared to untreated controls), with no restoration of follicle numbers evident after 7 days for either treatment. Furthermore, ovaries from mice subjected to sterilizing doses of γ-irradiation (0.45 or 4.5 Gy) revealed complete ablation of all primordial follicles 5 days after treatment, with no indication of follicular renewal. We conclude that neo-folliculogenesis does not occur following chemical or γ-irradiation mediated depletion of the primordial follicle reserve.

scholarly journals Ovarian Stem Cells–-the Pros and Cons

2013 ◽  
Vol 7 ◽  
pp. CMRH.S11086 ◽  
Author(s):  
Ayelet Evron ◽  
Zeev Blumenfeld
Keyword(s):  
Stem Cells ◽  
Cell Biology ◽  
De Novo ◽  
Germ Line ◽  
Mammalian Species ◽  
Primordial Follicle ◽  
Reproductive Age ◽  
Primordial Follicles ◽  
Pros And Cons ◽  
Reproductive Science

The potential for postnatal de novo oogenesis in mammals and in humans has become very controversial in the fields of reproductive science and biology. Historically, it has been thought that females of most mammalian species lose the ability to produce oocytes at birth. A contemporary understanding of stem cell biology together with novel experimental methods has challenged the model of a prenatal fixed ovarian primordial follicle pool that declines with age. Researchers have suggested replenishment of post-natal oocytes by germ-line stem cells (GSCs). According to this theory, GSCs produce oocytes and primordial follicles throughout the lifetime of the adult female. This review describes recent approaches supporting the revolutionary idea of de novo oogenesis in mammals and humans of reproductive-age and provides counter arguments from opponents of this novel and innovative concept.

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 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.

127. PUMA MEDIATES GERM CELL DEATH DURING OVARIAN DEVELOPMENT AND DETERMINES INITIAL PRIMORDIAL FOLLICLE NUMBER IN MICE

2010 ◽  
Vol 22 (9) ◽  
pp. 45
Author(s):  
F. Morgan ◽  
K. J. Hutt ◽  
C. L. Scott ◽  
M. Cook ◽  
A. Strasser ◽  
...  
Keyword(s):  
New York ◽  
Cell Death ◽  
Germ Cell ◽  
Germ Cells ◽  
Ovarian Reserve ◽  
Ovarian Development ◽  
Primordial Follicle ◽  
Primordial Follicles ◽  
Apoptotic Protein ◽  
Programmed Death

The proteins that control the number of primordial follicles initially established within the ovary are largely unknown. Here we investigated the hypothesis that PUMA, a pro-apoptotic protein belonging to the Bcl-2 family, regulates germ cell death during ovarian development and thereby determines the number of primordial follicles that make up the ovarian reserve. Ovaries were obtained from embryonic day 17.5 (E17.5) and post-natal day 10 (PN10) wild-type (wt) and puma–/– mice and subjected to morphological, molecular and stereological characterisation (n = 3-6 mice/genotype/age). At E17.5, ovaries were densely populated with germ cells and early meiotic oocytes. Immunostaining for MVH and PCNA confirmed the identity of germ cells and proliferating germ cells, respectively. Pyknotic nuclei and TUNEL positive germ cells were rarely detected, suggesting that cell death was uncommon at this age. At PN10, primordial follicle assembly was complete for both genotypes, as confirmed morphologically and by immunostaining for oocyte markers GCNA and MSY2. The number of germ cells in E17.5 wt and puma–/– ovaries was comparable (p=0.81, See Table 1). However, PN10 puma–/– ovaries contained significantly more primordial follicles than wt ovaries (P < 0.001, See Table 1), revealing an over-endowment of primordial follicles in the absence of PUMA. These data show that PUMA regulates the developmentally programmed death of germ cells between E17.5 and PN10 in the mouse and thereby determines the number of primordial follicles that make up the initial ovarian reserve. This work was supported by the NHMRC (Program Grants #494802 and #257502, Fellowships JKF (#441101), KJH (#494836), CLS (#406675), AS (#461299)); the Leukemia and Lymphoma Society (New York; SCOR grant#7015), the National Cancer Institute (NIH, US; CA80188 and CA43540) and Victorian Government Infrastructure Funds.

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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