scholarly journals The dynamics of the primordial follicle reserve

Reproduction ◽  
2013 ◽  
Vol 146 (6) ◽  
pp. R205-R215 ◽  
Author(s):  
Jeffrey B Kerr ◽  
Michelle Myers ◽  
Richard A Anderson
Keyword(s):  
Germ Cell ◽  
Large Scale ◽  
Indirect Evidence ◽  
Primordial Follicle ◽  
Genetically Engineered ◽  
Postnatal Life ◽  
Cell Dynamics ◽  
Primordial Follicles ◽  
Age Related ◽  
Female Germline

The female germline comprises a reserve population of primordial (non-growing) follicles containing diplotene oocytes arrested in the first meiotic prophase. By convention, the reserve is established when all individual oocytes are enclosed by granulosa cells. This commonly occurs prior to or around birth, according to species. Histologically, the ‘reserve’ is the number of primordial follicles in the ovary at any given age and is ultimately depleted by degeneration and progression through folliculogenesis until exhausted. How and when the reserve reaches its peak number of follicles is determined by ovarian morphogenesis and germ cell dynamics involving i) oogonial proliferation and entry into meiosis producing an oversupply of oocytes and ii) large-scale germ cell death resulting in markedly reduced numbers surviving as the primordial follicle reserve. Our understanding of the processes maintaining the reserve comes primarily from genetically engineered mouse models, experimental activation or destruction of oocytes, and quantitative histological analysis. As the source of ovulated oocytes in postnatal life, the primordial follicle reserve requires regulation of i) its survival or maintenance, ii) suppression of development (dormancy), and iii) activation for growth and entry into folliculogenesis. The mechanisms influencing these alternate and complex inter-related phenomena remain to be fully elucidated. Drawing upon direct and indirect evidence, we discuss the controversial concept of postnatal oogenesis. This posits a rare population of oogonial stem cells that contribute new oocytes to partially compensate for the age-related decline in the primordial follicle reserve.

scholarly journals Suppression of Notch Signaling in the Neonatal Mouse Ovary Decreases Primordial Follicle Formation

Endocrinology ◽  
2009 ◽  
Vol 150 (2) ◽  
pp. 1014-1024 ◽  
Author(s):  
Daniel J. Trombly ◽  
Teresa K. Woodruff ◽  
Kelly E. Mayo
Keyword(s):  
Germ Cell ◽  
Notch Signaling ◽  
Cell Fate ◽  
Germ Cells ◽  
Ex Vivo ◽  
Primordial Follicle ◽  
Neonatal Mouse ◽  
Postnatal Life ◽  
Mouse Ovary ◽  
Primordial Follicles

Notch signaling directs cell fate during embryogenesis by influencing cell proliferation, differentiation, and apoptosis. Notch genes are expressed in the adult mouse ovary, and roles for Notch in regulating folliculogenesis are beginning to emerge from mouse genetic models. We investigated how Notch signaling might influence the formation of primordial follicles. Follicle assembly takes place when germ cell syncytia within the ovary break down and germ cells are encapsulated by pregranulosa cells. In the mouse, this occurs during the first 4–5 d of postnatal life. The expression of Notch family genes in the neonatal mouse ovary was determined through RT-PCR measurements. Jagged1, Notch2, and Hes1 transcripts were the most abundantly expressed ligand, receptor, and target gene, respectively. Jagged1 and Hey2 mRNAs were up-regulated over the period of follicle formation. Localization studies demonstrated that JAGGED1 is expressed in germ cells prior to follicle assembly and in the oocytes of primordial follicles. Pregranulosa cells that surround germ cell nests express HES1. In addition, pregranulosa cells of primordial follicles expressed NOTCH2 and Hey2 mRNA. We used an ex vivo ovary culture system to assess the requirement for Notch signaling during early follicle development. Newborn ovaries cultured in the presence of γ-secretase inhibitors, compounds that attenuate Notch signaling, had a marked reduction in primordial follicles compared with vehicle-treated ovaries, and there was a corresponding increase in germ cells that remained within nests. These data support a functional role for Notch signaling in regulating primordial follicle formation. Gamma secretase inhibitor treatment suppresses germ cell nest breakdown in the neonatal mouse ovary, supporting a role for Notch signaling in promoting primordial follicle formation.

scholarly journals Follistatin Regulates Germ Cell Nest Breakdown and Primordial Follicle Formation

Endocrinology ◽  
2010 ◽  
Vol 152 (2) ◽  
pp. 697-706 ◽  
Author(s):  
Fuminori Kimura ◽  
Lara M. Bonomi ◽  
Alan L. Schneyer
Keyword(s):  
Germ Cell ◽  
Germ Cells ◽  
Ovarian Function ◽  
Primordial Follicle ◽  
Biochemical Properties ◽  
The Body ◽  
Protein Isoforms ◽  
Primordial Follicles ◽  
Reduced Rate ◽  
Regulatory Functions

Abstract Follistatin (FST) is an antagonist of activin and related TGFβ superfamily members that has important reproductive actions as well as critical regulatory functions in other tissues and systems. FST is produced as three protein isoforms that differ in their biochemical properties and in their localization within the body. We created FST288-only mice that only express the short FST288 isoform and previously reported that females are subfertile, but have an excess of primordial follicles on postnatal day (PND) 8.5 that undergo accelerated demise in adults. We have now examined germ cell nest breakdown and primordial follicle formation in the critical PND 0.5–8.5 period to test the hypothesis that the excess primordial follicles derive from increased proliferation and decreased apoptosis during germ cell nest breakdown. Using double immunofluorescence microscopy we found that there is virtually no germ cell proliferation after birth in wild-type or FST288-only females. However, the entire process of germ cell nest breakdown was extended in time (through at least PND 8.5) and apoptosis was significantly reduced in FST288-only females. In addition, FST288-only females are born with more germ cells within the nests. Thus, the excess primordial follicles in FST288-only mice derive from a greater number of germ cells at birth as well as a reduced rate of apoptosis during nest breakdown. These results also demonstrate that FST is critical for normal regulation of germ cell nest breakdown and that loss of the FST303 and/or FST315 isoforms leads to excess primordial follicles with accelerated demise, resulting in premature cessation of ovarian function.

scholarly journals PUMA regulates germ cell loss and primordial follicle endowment in mice

Reproduction ◽  
2014 ◽  
Vol 148 (2) ◽  
pp. 211-219 ◽  
Author(s):  
Michelle Myers ◽  
F Hamish Morgan ◽  
Seng H Liew ◽  
Nadeen Zerafa ◽  
Thilini Upeksha Gamage ◽  
...  
Keyword(s):  
Cell Death ◽  
Germ Cell ◽  
Germ Cells ◽  
Ovarian Development ◽  
Fold Increase ◽  
Cell Loss ◽  
Postnatal Life ◽  
Critical Determinant ◽  
Primordial Follicles ◽  
Female Mice

The number of primordial follicles initially established within the ovary is influenced by the extent of germ cell death during foetal ovarian development, but the mechanisms that mediate this death have not been fully uncovered. In this study, we identified BBC3 (PUMA) (p53 upregulated modulator of apoptosis, also known as BCL2-binding component 3), a pro-apoptotic BH3-only protein belonging to the BCL2 family, as a critical determinant of the number of germ cells during ovarian development. Targeted disruption of the Bbc3 gene revealed a significant increase in the number of germ cells as early as embryonic day 13.5. The number of germ cells remained elevated in Bbc3−/− female mice compared with WT female mice throughout the remainder of embryonic and early postnatal life, resulting in a 1.9-fold increase in the number of primordial follicles in the ovary on postnatal day 10. The increase in the number of germ cells observed in the ovaries of Bbc3−/− mice could not be attributed to the altered proliferative activity of germ cells within the ovaries. Furthermore, BBC3 was found to be not required for the massive germ cell loss that occurs during germ cell nest breakdown. Our data indicate that BBC3 is a critical regulator of germ cell death that acts during the migratory phase of oogenesis or very soon after the arrival of germ cells in the gonad and that BBC3-mediated cell death limits the number of primordial follicles established in the initial ovarian reserve.

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 Reproductive Longevity and Aging: Geroscience Approaches to Maintain Long-Term Ovarian Fitness

2020 ◽  
Author(s):  
Natalia Llarena ◽  
Christopher Hine
Keyword(s):  
Ovarian Reserve ◽  
Ovarian Function ◽  
Reproductive Function ◽  
Primordial Follicle ◽  
Oocyte Quality ◽  
Nutrient Sensing ◽  
Primordial Follicles ◽  
Age Related ◽  
Reproductive Life ◽  
Reproductive Life Span

Abstract Increases in delayed childbearing worldwide have elicited the need for a better understanding of the biological underpinnings and implications of age-related infertility. In women 35 years and older the incidences of infertility, aneuploidy, and birth defects dramatically increase. These outcomes are a result of age-related declines in both ovarian reserve and oocyte quality. In addition to waning reproductive function, the decline in estrogen secretion at menopause contributes to multisystem aging and the initiation of frailty. Both reproductive and hormonal ovarian function are limited by the primordial follicle pool, which is established in utero and declines irreversibly until menopause. Because ovarian function is dependent on the primordial follicle pool, an understanding of the mechanisms that regulate follicular growth and maintenance of the primordial follicle pool is critical for the development of interventions to prolong the reproductive life span. Multiple pathways related to aging and nutrient-sensing converge in the mammalian ovary to regulate quiescence or activation of primordial follicles. The PI3K/PTEN/AKT/FOXO3 and associated TSC/mTOR pathways are central to the regulation of the primordial follicle pool; however, aging-associated systems such as the insulin-like growth factor-1/growth hormone pathway, and transsulfuration/hydrogen sulfide pathways may also play a role. Additionally, sirtuins aid in maintaining developmental metabolic competence and chromosomal integrity of the oocyte. Here we review the pathways that regulate ovarian reserve and oocyte quality, and discuss geroscience interventions that leverage our understanding of these pathways to promote reproductive longevity.

scholarly journals Quantification of healthy follicles in the neonatal and adult mouse ovary: evidence for maintenance of primordial follicle supply

Reproduction ◽  
2006 ◽  
Vol 132 (1) ◽  
pp. 95-109 ◽  
Author(s):  
J B Kerr ◽  
R Duckett ◽  
M Myers ◽  
K L Britt ◽  
T Mladenovska ◽  
...  
Keyword(s):  
Stem Cells ◽  
Primordial Follicle ◽  
Meiotic Maturation ◽  
Nuclear Antigen ◽  
Surface Epithelium ◽  
Postnatal Life ◽  
Germline Stem Cells ◽  
Primordial Follicles ◽  
Oocyte Meiosis ◽  
Mitotic Figures

Proliferation and partial meiotic maturation of germ cells in fetal ovaries is believed to establish a finite, non-renewable pool of primordial follicles at birth. The supply of primordial follicles in postnatal life should be depleted during folliculogenesis, either undergoing atresia or surviving to ovulation. Recent studies of mouse ovaries propose that intra- and extraovarian germline stem cells replenish oocytes and form new primordial follicles. We quantified all healthy follicles in C57BL/6 mouse ovaries from day 1 to 200 using unbiased stereological methods, immunolabelling of oocyte meiosis (germ cell nuclear antigen (GCNA)) and ovarian cell proliferation (proliferating cell nuclear antigen (PCNA)) and electronmicroscopy. Day 1 ovaries contained 7924±1564 (s.e.m.) oocytes or primordial follicles, declining on day 7 to 1987±203, with 200–800 oocytes ejected from individual ovaries on that day and day 12. Discarded oocytes and those subjacent to the surface epithelium were GCNA-positive indicating their incomplete meiotic maturation. From day 7 to 100 mean numbers of primordial follicles per ovary were not significantly depleted but declined at 200 days to 254±71. Mean numbers of all healthy follicles per ovary were not significantly different from day 7 to 100 (range 2332±349–3007±322). Primordial follicle oocytes were PCNA-negative. Occasional unidentified cells were PCNA-positive with mitotic figures observed in the cortex of day 1 and 12 ovaries. Although we found no evidence for ovarian germline stem cells, our data support the hypothesis of postnatal follicle renewal in postnatal and adult ovaries of C57BL/6 mice.

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 Antioxidant supplementation partially rescues accelerated ovarian follicle loss, but not oocyte quality, of glutathione-deficient mice†

2020 ◽  
Vol 102 (5) ◽  
pp. 1065-1079
Author(s):  
Jinhwan Lim ◽  
Samiha Ali ◽  
Lisa S Liao ◽  
Emily S Nguyen ◽  
Laura Ortiz ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lipoic Acid ◽  
Ovarian Follicle ◽  
Primordial Follicle ◽  
Oocyte Quality ◽  
Embryonic Mortality ◽  
Wild Type ◽  
Primordial Follicles ◽  
Age Related ◽  
Acetyl Cysteine

Abstract The tripeptide thiol antioxidant glutathione (GSH) has multiple physiological functions. Female mice lacking the modifier subunit of glutamate cysteine ligase (GCLM), the rate-limiting enzyme in GSH synthesis, have decreased GSH concentrations, ovarian oxidative stress, preimplantation embryonic mortality, and accelerated age-related decline in ovarian follicles. We hypothesized that supplementation with thiol antioxidants, N-acetyl cysteine (NAC), or α-lipoic acid (ALA) will rescue this phenotype. Gclm−/− and Gclm+/+ females received 0 or 80 mM NAC in drinking water from postnatal day (PND) 21–30; follicle growth was induced with equine chorionic gonadotropin (eCG) on PND 27, followed by an ovulatory dose of human CG and mating with a wild type male on PND 29 and zygote harvest 20 h after hCG. N-acetyl cysteine supplementation failed to rescue the low rate of second pronucleus formation in zygotes from Gclm−/− versus Gclm+/+ females. In the second study, Gclm−/− and Gclm+/+ females received diet containing 0, 150, or 600 mg/kg ALA beginning at weaning and were mated with wild type males from 8 to 20 weeks of age. α-Lipoic acid failed to rescue the decreased offspring production of Gclm−/− females. However, 150 mg/kg diet ALA partially rescued the accelerated decline in primordial follicles, as well as the increased recruitment of follicles into the growing pool and the increased percentages of follicles with γH2AX positive oocytes or granulosa cells of Gclm−/− females. We conclude that ovarian oxidative stress is the cause of accelerated primordial follicle decline, while GSH deficiency per se may be responsible for preimplantation embryonic mortality in Gclm−/− females.

scholarly journals Transcriptome Landscape Reveals Underlying Mechanisms of Ovarian Cell Fate Differentiation and Primordial Follicle Assembly

2019 ◽  
Author(s):  
Jun-Jie Wang ◽  
Wei Ge ◽  
Qiu-Yue Zhai ◽  
Jing-Cai Liu ◽  
Xiao-Wen Sun ◽  
...  
Keyword(s):  
Germ Cell ◽  
Single Cell ◽  
Cell Fate ◽  
Germ Cells ◽  
Granulosa Cells ◽  
Primordial Follicle ◽  
Gene Clusters ◽  
Bioinformatics Analyses ◽  
Primordial Follicles ◽  
New Genes

AbstractPrimordial follicle assembly in mammals occurs at perinatal ages and largely determines the ovarian reserve available to support the reproductive lifespan. The primordial follicle structure is generated by a complex network of interactions between oocytes and ovarian somatic cells that remain poorly understood. In the present research, using single-cell RNA sequencing performed over a time-series on mouse ovaries coupled with several bioinformatics analyses, the complete dynamic genetic programs of germ and granulosa cells from E16.5 to PD3 are reported for the first time. The time frame of analysis comprises the breakdown of germ cell cysts and the assembly of primordial follicles. Confirming the previously reported expression of genes by germ cells and granulosa cells, our analyses identified ten distinct gene clusters associated to germ cells and eight to granulosa cells. Consequently, several new genes expressed at significant levels at each investigated stage were assigned. Building single-cell pseudo temporal trajectories five states and two branch points of fate transition for the germ cells, and three states and one branch point for the granulosa cells were revealed. Moreover, GO and ClueGO term enrichment enabled identifying biological processes, molecular functions and cellular components more represented in germ cells and granulosa cells or common to both cell types at each specific stage. Finally, by SCENIC algorithm, we were able to establish a network of regulons that can be postulated as likely candidates for sustaining germ cell specific transcription programs throughout the investigated period.

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