Germ Cell Proliferation and Apoptosis in the Developing Human Ovary

Fulton, Norma; Silva, Sarah Martins da; Bayne, Rosemary A. L.; Anderson, Richard A.

doi:10.1210/jc.2005-0219

Cited by 82 publications

(73 citation statements)

References 46 publications

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“…At later gestations (beyond 12-13 wga), germ cells at various stages of differentiation are seen in the same ovary, arising from considerable asynchrony in the progression of human fetal ovarian germ cell development [22,23]. Mitotic PGC-like cells are restricted to the periphery of the ovary, with progressively more differentiated germ cells found in a gradient toward the center [22][23][24].…”

Section: Resultsmentioning

confidence: 99%

LIN28 Is Selectively Expressed by Primordial and Pre-Meiotic Germ Cells in the Human Fetal Ovary

Childs

Kinnell

et al. 2012

Stem Cells and Development

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Germ cell development requires timely transition from primordial germ cell (PGC) self-renewal to meiotic differentiation. This is associated with widespread changes in gene expression, including downregulation of stem cell-associated genes, such as OCT4 and KIT, and upregulation of markers of germ cell differentiation and meiosis, such as VASA, STRA8, and SYCP3. The stem cell-expressed RNA-binding protein Lin28 has recently been demonstrated to be essential for PGC specification in mice, and LIN28 is expressed in human germ cell tumors with phenotypic similarities to human fetal germ cells. We have therefore examined the expression of LIN28 during normal germ cell development in the human fetal ovary, from the PGC stage, through meiosis to the initiation of follicle formation. LIN28 transcript levels were highest when the gonad contained only PGCs, and decreased significantly with increasing gestation, coincident with the onset of germ cell differentiation. Immunohistochemistry revealed LIN28 protein expression to be germ cell-specific at all stages examined. All PGCs expressed LIN28, but at later gestations expression was restricted to a subpopulation of germ cells, which we demonstrate to be primordial and premeiotic germ cells based on immunofluorescent colocalization of LIN28 and OCT4, and absence of overlap with the meiosis marker SYCP3. We also demonstrate the expression of the LIN28 target precursor pri-microRNA transcripts pri-LET7a/f/d and pri-LET-7g in the human fetal ovary, and that expression of these is highest at the PGC stage, mirroring that of LIN28. The spatial and temporal restriction of LIN28 expression and coincident peaks of expression of LIN28 and target pri-microRNAs suggest important roles for this protein in the maintenance of the germline stem cell state and the regulation of microRNA activity in the developing human ovary.

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Section: Resultsmentioning

confidence: 99%

LIN28 Is Selectively Expressed by Primordial and Pre-Meiotic Germ Cells in the Human Fetal Ovary

Childs

Kinnell

et al. 2012

Stem Cells and Development

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“…Much attention has focused on apoptosis (Vaskivuo et al 2001, Fulton et al 2005, Poljicanin et al 2012, although emerging evidence also suggests that the mode of germ cell elimination, especially in meiosis, may be ovary specific and occurs by several mechanisms not limited to the classical apoptotic pathways (Abir et al 2002). Efforts to identify and quantitate the characteristics of apoptosis as a principal or coherent explanation for oocyte depletion in the human fetal ovary often demonstrate the difficulties and inconsistencies in interpretation of cause and effect, probably due to differential gene expression among cell populations that may be at rest, proliferating, maturing, dying, or phagocytosing (Kurilo 1981, De Pol et al 1997, Vaskivuo et al 2001, Abir et al 2002, Fulton et al 2005, Stoop et al 2005, Albamonte et al 2008, Jaaskelainen et al 2010, Boumela et al 2011, Poljicanin et al 2012. Nevertheless, these and other studies demonstrate that the Bcl2 gene family is an important regulator (among other factors) of the balance between survival or death of oocytes prior to primordial follicle formation.…”

Section: Establishing the Primordial Follicle Reservementioning

confidence: 99%

“…Meiotic entry is not an 'all-or-none' event but a gradual process occurring from e13.5 to e18.5 (Peters et al 1962, Ghafari et al 2007) and progressing in the ovary in a cranialcaudal direction (Bullejos & Koopman 2004). Many oogonia in the fetal mouse (and human) ovary continue mitosis while others enter meiotic prophase (Evans 1982, Fulton et al 2005) and therefore oogonia with fewer or greater numbers of mitotic divisions would respectively transit early or later into meiosis. Medullary oocytes become early activated primordial follicles but cortexresident oocytes are delayed in their assembly as primordial follicles (Fig.…”

Section: The Primordial Follicle Reserve: Is It Renewable?mentioning

confidence: 99%

The dynamics of the primordial follicle reserve

Kerr¹,

Myers²,

Anderson³

2013

Reproduction

128

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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.Reproduction (2013) 146 R205-R215

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“…In rodents follicle assembly occurs in the first few days after birth (Peters & Byskov 1975, Cran & Moor 1980, Hirshfield 1991, Rajah & Glaser 1992. In humans, follicle assembly begins during midgestation near week 18 and continues into the third trimester (Baker 1963, Fulton & Martins da Silva 2005. The size (i.e.…”

Section: Introductionmentioning

confidence: 99%

Interactions between progesterone and tumor necrosis factor-α in the regulation of primordial follicle assembly

Nilsson

Stanfield²,

Skinner

2006

Reproduction

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Follicle assembly is the process by which groups or 'nests' of oocytes break down to form primordial follicles. The size of the primordial follicle pool is the major determinant of the reproductive lifespan of a female. Previously, progesterone (P 4 ) has been shown to inhibit follicle assembly, while tumor necrosis factor-a (TNFa) has been shown to promote the apoptosis that is necessary for follicle assembly. The present study examines how TNFa and progesterone interact to regulate primordial follicle assembly. Ovaries were collected from newborn rats and placed in organ culture to examine the actions of P 4 and TNFa. P 4 was found to decrease primordial follicle assembly and increase the percentage of unassembled oocytes both in vitro and in vivo. TNFa treatment did not change the proportion of assembled follicles in cultured ovaries, but blocked the ability of P 4 to inhibit follicle assembly. Microarray analysis of the ovarian transcriptome revealed that progesterone treatment of the ovaries altered the expression of 513 genes with 132 only expressed after P 4 treatment and 16 only expressed in control ovaries. The majority of genes were up-regulated greater than twofold over control, with a small subset of 16 genes down-regulated. Categories of genes affected by P 4 are described including a group of extracellular signaling factors. The progesterone receptors expressed at the time of follicle assembly included the surface membrane progesterone receptors PGRMC1, PGRMC2, and RDA288. The nuclear genomic P 4 receptor was not expressed at appreciable levels. Progesterone increased the expression of several genes (TANK, NFkB, Bcl2l1, and Bcl2l2) involved in a signaling pathway that promotes cell survival and inhibits apoptosis. Observations indicate that P 4 acts through the surface membrane progesterone receptors to regulate primordial follicle assembly, and that TNFa can override the inhibitory actions of P 4 on follicle assembly. A major mechanism involved in the actions of P 4 is an increase in cell survival genes and inhibition of the apoptosis pathway. Observations provide insight into the hormonal regulation of primordial follicle assembly and lead to novel approaches to potentially manipulate follicle assembly and reproductive capacity.

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Germ Cell Proliferation and Apoptosis in the Developing Human Ovary

Abstract: These results indicate that as primordial follicle formation is initiated and progresses, there is an increase in both mitotic activity and apoptosis of those germ cells that have not reached the apparently protective environment of the primordial follicle.

Cited by 82 publications

References 46 publications

LIN28 Is Selectively Expressed by Primordial and Pre-Meiotic Germ Cells in the Human Fetal Ovary

LIN28 Is Selectively Expressed by Primordial and Pre-Meiotic Germ Cells in the Human Fetal Ovary

The dynamics of the primordial follicle reserve

Interactions between progesterone and tumor necrosis factor-α in the regulation of primordial follicle assembly

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