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 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 Altered germline cyst and oocyte differentiation in Tex14 mutant mice reveal a new mechanism underlying female reproductive life-span

2019 ◽  
Author(s):  
Nafisa Nuzhat ◽  
Kanako Ikami ◽  
Haley Abbott ◽  
Heather Tanner ◽  
Allan C. Spradling ◽  
...  
Keyword(s):  
Germ Cells ◽  
Ovarian Function ◽  
Primordial Follicle ◽  
Wild Type ◽  
Developmental Potential ◽  
Primordial Follicles ◽  
Intercellular Bridges ◽  
Reproductive Life ◽  
Reproductive Life Span ◽  
Oocyte Differentiation

AbstractIn adult mammalian females, primordial follicles that form in the fetal/neonatal ovary are the only source to sustain adult ovarian function. Our previous studies revealed that during oocyte differentiation and primordial follicle formation in mouse fetal ovaries, primary oocytes form via gaining cytoplasm and organelles from sister germ cells that are connected to them by intercellular bridges within germline cysts. To better understand the role of intercellular bridges in oocyte differentiation, we analyzed mutant females lacking testis-expressed 14 (Tex14), a gene involved in cytokinesis and bridge formation. In Tex14-/- fetal ovaries, germ cells divide to form a reduced number of cysts in which sister germ cells are still connected via syncytia or fragmented cell membranes, rather than normal intercellular bridges. Compared with wildtype cysts, Tex14-/- cysts fragment at a higher frequency and produce a greatly reduced number of primary oocytes with highly precocious cytoplasmic enrichment and enlarged volume. By contrast, Tex14+/- germline cysts are less fragmented and generate primary oocytes that are smaller than wild type. Interestingly, enlarged Tex14-/- primary oocytes are much more stable than wild type oocytes and more efficiently sustain folliculogenesis, whereas undersized Tex14+/- primary oocytes turn over at an accelerated rate. Our observations directly link the nature of fetal germ cell connectivity to cytoplasmic enrichment during oocyte differentiation and to oocyte developmental potential in the adult ovary. Our results imply that the duration of adult ovarian function is strongly influenced by the number of primary oocytes acquiring highly enriched cytoplasm during oocyte differentiation in fetal ovaries, rather than just by the size of the primordial follicle pool.

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 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.

scholarly journals PI3K/PTEN/AKT Signaling Pathways in Germ Cell Development and Their Involvement in Germ Cell Tumors and Ovarian Dysfunctions

2021 ◽  
Vol 22 (18) ◽  
pp. 9838
Author(s):  
Massimo De Felici ◽  
Francesca Gioia Klinger
Keyword(s):  
Germ Cell ◽  
Signaling Pathways ◽  
Ovarian Function ◽  
Primordial Germ Cells ◽  
Primordial Germ Cell ◽  
Germ Cell Tumors ◽  
Primordial Follicle ◽  
Akt Signaling ◽  
Cell Development ◽  
Germ Cell Development

Several studies indicate that the PI3K/PTEN/AKT signaling pathways are critical regulators of ovarian function including the formation of the germ cell precursors, termed primordial germ cells, and the follicular pool maintenance. This article reviews the current state of knowledge of the functional role of the PI3K/PTEN/AKT pathways during primordial germ cell development and the dynamics of the ovarian primordial follicle reserve and how dysregulation of these signaling pathways may contribute to the development of some types of germ cell tumors and ovarian dysfunctions.

Memoirs: Studies on the Germ-cell Cycle of Cryptocotyle lingua

1934 ◽  
Vol s2-76 (304) ◽  
pp. 573-614
Author(s):  
RAYMOND MILLARD CABLE
Keyword(s):  
Cell Cycle ◽  
Germ Cell ◽  
Germ Cells ◽  
Alternative Hypothesis ◽  
Primordial Germ Cells ◽  
Body Cavity ◽  
The Body ◽  
Larval Stages ◽  
Nuclear Changes ◽  
New Hosts

The writer's earlier study (Cable, 1931) on the germ-cell cycle in the adult stage of Cryptocotyle lingua is supplemented by an investigation of germinal development in the larval stages occurring in the marine snail, Littorina littorea. The miracidium-mother-sporocyst was not found although very young rediae were abundant in the material studied. The primordial germ-cells of the young redia are observed in an undifferentiated condition in the body-cavity, which is not well defined due to an abundance of connective tissue. After a period of differentiation, including growth, progressive nuclear changes, and condensation of cytoplasm, the germ-cells multiply by equal division, a process which is interpreted as polyembryony. Germinal differentiation exhibits a distinct anterior-posterior gradient. The mature germinal cells give rise directly to cercarial embryos without germ-mass formation and dissociation or any maturation processes. Although germinal lineage may be traced in the redia, it seems to be interrupted in the cercaria, due to delayed segregation of germ-cells. The soma of the redia does not produce germ-cells at any stage. Evidence is afforded by this and other studies that germinal lineage with sudden intercalations of polyembryonic stages (germ-masses) cannot explain the germinal cycle of the trematodes as a group. In an alternative hypothesis, based on the phylogeny of the Digenea, it is suggested that the ancestors of this group became sexually mature in the mollusc and completed the cycle in that host, possibly before the appearance of vertebrates; and that, with the evolution of the trematodes, sexual phenomena have gradually been lost, while accessory stages and new hosts have been included in the life-cycle. Cryptocotyle lingua is assumed to have been modified to an intermediate extent since sexual reproduction, germ-masses, and the maximum number of intercalary stages are lacking in the larval generations.

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.

Expression of Bcl-2 and 3-ß hydroxysteroid dehydrogenase protein during oocyte and follicle development in fetal and post-natal pig ovaries

1999 ◽  
Vol 11 (8) ◽  
pp. 463 ◽  
Author(s):  
Wesley M. Garrett ◽  
H. David Guthrie
Keyword(s):  
Cell Proliferation ◽  
Germ Cell ◽  
Germ Cells ◽  
Granulosa Cells ◽  
Stromal Cells ◽  
Post Partum ◽  
Nuclear Antigen ◽  
Ki 67 ◽  
Primordial Follicles ◽  
Small Clusters

The fetal and post-natal development of the pig ovary involves both proliferation and apoptotic loss of germ cells, follicle formation and growth, and the initiation of oocyte meiotic maturation. The present study measured the expression of the proto-oncogene Bcl-2 immunohistochemically on paraffin sections of pig ovaries to determine its relationship with folliculogenesis on Days 50 and 80 post coitum (p.c.) and on Days 1, 21, and 56 post partum (p.p.). The expression of the steroidogenic enzyme 3β-hydroxy-steroid dehydrogenase (3βHSD) was used to determine the lineages of the cells forming the ovarian follicles, and the expression of the cell proliferation-associated nuclear antigen Ki-67 was used to determine germ cell proliferation and the initiation of follicle growth. Expression of Ki-67 showed that many oogonia were proliferating on Days 50 and 80 p.c. Granulosa cells were more proliferative on Day 56 p.p. than at any other stage; Ki-67 was expressed in 70% of growing follicles and granulosa cells had a 3% mean staining index per section. Less than 4% of germ cells and follicles had morphological signs of degeneration during the period of the study. Bcl-2 was most abundant on Days 21 p.p. and 56 p.p.; staining was localized to stromal cells among follicles and in small clusters in the cortical–medullary junction (CMJ). 3βHSD staining on Day 50 p.c. was seen in cords of stromal cells within the medulla of the ovary, and in the stromal cells investing the oogonial nests. On Days 80 p.c., 1 p.p., 21 p.p., and 56 p.p., 3βHSD was expressed in the granulosa cells of primary or primordial follicles at the CMJ. Production of Bcl-2 by somatic cells may support germ cell and preantral follicle survival.

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 Metformin: a novel promising option for fertility preservation during cyclophosphamide-based chemotherapy

2021 ◽  
Author(s):  
Chu-Chun Huang ◽  
Chia-Hung Chou ◽  
Yu-Shih Yang ◽  
Hong-Nerng Ho ◽  
Chia-Tung Shun ◽  
...  
Keyword(s):  
Ovarian Function ◽  
Primordial Follicle ◽  
Inhibitory Effect ◽  
Metformin Treatment ◽  
High Power Field ◽  
Primordial Follicles ◽  
Apoptotic Effect ◽  
Apoptotic Effects

Abstract Cyclophosphamide (CP) could cause severe gonadotoxicity via imbalanced activation of primordial follicles through PI3K/AKT/mTOR activation. Whether metformin, a widely prescribed anti-diabetes agent with mTOR inhibitory effect, could preserve ovarian function against CP toxicity is unknown. Female C57BL/6 mice were randomized into seven groups (n = 11), including control, CP-alone, CP+metformin, CP+sirolimus or everolimus, metformin-alone and sirolimus-alone groups. The duration of pharmaceutical treatment was four weeks. CP treatment significantly impaired ovarian function and fertility in mice. CP+metformin treatment significantly attenuated the gonadotoxicity comparing to CP-alone treatment (Primordial follicle count: 17.6 ± 4.2 versus 10.3 ± 2.7 follicles/high-power field; p = 0.027). CP+metformin treatment also tended to increase antral follicular count (5.4 ± 1.1 versus 2.5 ± 1.6 follicles/section), serum AMH levels (4.6 ± 1.2 versus 2.0 ± 0.8 ng/ml) and the litter size (4.2 ± 1.3 versus 1.5 ± 1.0 mice per pregnancy), compared with CP-alone group. Expression of phospho-mTOR and the number of TUNEL-positive granulosa cells increased after CP treatment and decreased in the CP+metformin groups, suggesting the mTOR inhibitory and anti-apoptotic effects of metformin. In in vitro granulosa cell experiments, the anti-apoptotic effect of metformin was blocked after inhibiting p53 or p21 function, and the expression of p53 mRNA was blocked with AMPK inhibitor, suggesting that the anti-apoptotic effect was AMPK/p53/p21-mediated. In conclusion, concurrent metformin treatment during CP therapy could significantly preserve ovarian function and fertility and could be a promising novel fertility preserving agent during chemotherapy. The relatively acceptable cost and well-established long-term safety profiles of this old drug might prompt its further clinical application at a faster pace.

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