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Journal ArticleDOI

Regulation of germ cell development by intercellular signaling in the mammalian ovarian follicle.

01 Jan 2018-Wiley Interdisciplinary Reviews-Developmental Biology (John Wiley & Sons, Ltd)-Vol. 7, Iss: 1
TL;DR: Oocyte differentiation depends on continuous signaling interactions with the somatic cells of the follicle and may be regulated by extracellular vesicles newly identified in follicular fluid and at TZP tips, which could mediate intercellular transfer of macromolecules.
Abstract: Prior to ovulation, the mammalian oocyte undergoes a process of differentiation within the ovarian follicle that confers on it the ability to give rise to an embryo. Differentiation comprises two phases-growth, during which the oocyte increases more than 100-fold in volume as it accumulates macromolecules and organelles that will sustain early embryogenesis; and meiotic maturation, during which the oocyte executes the first meiotic division and prepares for the second division. Entry of an oocyte into the growth phase appears to be triggered when the adjacent granulosa cells produce specific growth factors. As the oocyte grows, it elaborates a thick extracellular coat termed the zona pellucida. Nonetheless, cytoplasmic extensions of the adjacent granulosa cells, termed transzonal projections (TZPs), enable them to maintain contact-dependent communication with the oocyte. Through gap junctions located where the TZP tips meet the oocyte membrane, they provide the oocyte with products that sustain its metabolic activity and signals that regulate its differentiation. Conversely, the oocyte secretes diffusible growth factors that regulate proliferation and differentiation of the granulosa cells. Gap junction-permeable products of the granulosa cells prevent precocious initiation of meiotic maturation, and the gap junctions also enable oocyte maturation to begin in response to hormonal signals received by the granulosa cells. Development of the oocyte or the somatic compartment may also be regulated by extracellular vesicles newly identified in follicular fluid and at TZP tips, which could mediate intercellular transfer of macromolecules. Oocyte differentiation thus depends on continuous signaling interactions with the somatic cells of the follicle. WIREs Dev Biol 2018, 7:e294. doi: 10.1002/wdev.294 This article is categorized under: Gene Expression and Transcriptional Hierarchies > Cellular Differentiation Signaling Pathways > Cell Fate Signaling Early Embryonic Development > Gametogenesis.

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Citations
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07 Nov 2005
TL;DR: Because experimentally induced breakdown of communication within the ovarian follicle is associated with a drop in intraoocyte cAMP concentrations and results in resumption of meiosis, this could be the physiological mechanism employed by LH to stimulate oocyte maturation.
Abstract: Meiotically arrested mammalian oocytes are stimulated to resume meiosis by LH. This response, which can be reversed by elevation of intraoocyte cAMP levels, is associated with interruption of gap junctional communication (GJC) within the ovarian follicle. In the present study, we examined the hypothesis that disruption of GJC within the ovarian follicle is sufficient for induction of oocyte maturation. For this purpose, we incubated rat follicle-enclosed oocytes with carbenoxolone (CBX), a known blocker of gap junctions. We found that this selective disruptor of GJC promoted maturation of almost all the follicle-enclosed oocytes after 5 h of incubation; this response was also obtained by a transient (2 h) exposure to this agent. CBX-induced oocyte maturation was accompanied by a substantial decrease in intraoocyte concentrations of cAMP that was not associated with elevated activity of type 3A phosphodiesterase (PDE3A). The effect of CBX on reinitiation of meiosis was blocked by isobutylmethylxanthine, a phosphodiesterase inhibitor. Unlike LH, CBX did not activate MAPK in the follicular cells, and inhibition of the MAPK signaling pathway by means of UO126 did not prevent the resumption of meiosis. Injection of CBX into the ovarian bursa of intact animals stimulated maturation in 30% of the oocytes, whereas no maturation was observed in the contralateral ovary injected with PBS. We conclude that, because experimentally induced breakdown of communication within the ovarian follicle is associated with a drop in intraoocyte cAMP concentrations and results in resumption of meiosis, this could be the physiological mechanism employed by LH to stimulate oocyte maturation.

167 citations

Journal ArticleDOI
TL;DR: It is shown that conditional knockout (cKO) of Mtor in either primordial or growing oocytes caused infertility but differentially affected oocyte quality, granulosa cell fate, and follicular development.
Abstract: MTOR (mechanistic target of rapamycin) is a widely recognized integrator of signals and pathways key for cellular metabolism, proliferation, and differentiation. Here we show that conditional knockout (cKO) of Mtor in either primordial or growing oocytes caused infertility but differentially affected oocyte quality, granulosa cell fate, and follicular development. cKO of Mtor in nongrowing primordial oocytes caused defective follicular development leading to progressive degeneration of oocytes and loss of granulosa cell identity coincident with the acquisition of immature Sertoli cell-like characteristics. Although Mtor was deleted at the primordial oocyte stage, DNA damage accumulated in oocytes during their later growth, and there was a marked alteration of the transcriptome in the few oocytes that achieved the fully grown stage. Although oocyte quality and fertility were also compromised when Mtor was deleted after oocytes had begun to grow, these occurred without overtly affecting folliculogenesis or the oocyte transcriptome. Nevertheless, there was a significant change in a cohort of proteins in mature oocytes. In particular, down-regulation of PRC1 (protein regulator of cytokinesis 1) impaired completion of the first meiotic division. Therefore, MTOR-dependent pathways in primordial or growing oocytes differentially affected downstream processes including follicular development, sex-specific identity of early granulosa cells, maintenance of oocyte genome integrity, oocyte gene expression, meiosis, and preimplantation developmental competence.

95 citations

Journal Article
TL;DR: It is proposed that the basement membrane and/or theca cells that surround the follicle provide an important confinement for rapidly dividing columnar cells so that they attain maximum packing density, which restricts lateral mitosis and promotes inwardly oriented cell divisions and subsequent multilayering.
Abstract: 1. 1. Da Silva-Buttkus P., 2. et al. 2008. J. Cell Sci. doi:10.1242/jcs.036400 [OpenUrl][1][Abstract/FREE Full Text][2] [1]: {openurl}?query=rft.jtitle%253DJ.%2BCell%2BSci.%26rft_id%253Dinfo%253Adoi%252F10.1242%252Fjcs.036400%26rft_id%253Dinfo%253Apmid%252F19001500%26rft

87 citations

Journal ArticleDOI
TL;DR: Several key players that regulate FSH synthesis, sorting, secretion and action in gonads and extragonadal tissues have been identified in a physiological setting and it is anticipated that several exciting new discoveries uncovering all aspects of FSH biology will soon be forthcoming.
Abstract: Follicle-stimulating hormone (FSH) plays fundamental roles in male and female fertility. FSH is a heterodimeric glycoprotein expressed by gonadotrophs in the anterior pituitary. The hormone-specific FSHβ-subunit is non-covalently associated with the common α-subunit that is also present in the luteinizing hormone (LH), another gonadotrophic hormone secreted by gonadotrophs and thyroid-stimulating hormone (TSH) secreted by thyrotrophs. Several decades of research led to the purification, structural characterization and physiological regulation of FSH in a variety of species including humans. With the advent of molecular tools, availability of immortalized gonadotroph cell lines and genetically modified mouse models, our knowledge on molecular mechanisms of FSH regulation has tremendously expanded. Several key players that regulate FSH synthesis, sorting, secretion and action in gonads and extragonadal tissues have been identified in a physiological setting. Novel post-transcriptional and post-translational regulatory mechanisms have also been identified that provide additional layers of regulation mediating FSH homeostasis. Recombinant human FSH analogs hold promise for a variety of clinical applications, whereas blocking antibodies against FSH may prove efficacious for preventing age-dependent bone loss and adiposity. It is anticipated that several exciting new discoveries uncovering all aspects of FSH biology will soon be forthcoming.

76 citations


Cites background from "Regulation of germ cell development..."

  • ...2004), gap junction proteins between granulosa cells (El-Hyek & Clarke 2015, Clarke 2018) and epidermal growth factor receptor expression in granulosa cells to prime the follicles for ovulation prior to LH action (El-Hayek et al....

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Journal ArticleDOI
TL;DR: It is shown that TZP number and germline-soma communication are strikingly reduced in reproductively aged females, and an inability of somatic follicle cells to respond appropriately to oocyte-derived cues may contribute to human infertility.

70 citations


Cites background from "Regulation of germ cell development..."

  • ...On one hand, the granulosa cells send signals that trigger oocytes in primordial follicles to initiate growth, provide essential metabolites to growing oocytes, and regulate entry of fully grown oocytes into meiotic maturation [10, 16, 26, 27]....

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  • ...TZPs Are Specialized Filopodia Prior to ovulation and fertilization, mammalian oocytes undergo a prolonged period of growth within the ovarian follicle [16]....

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References
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Journal ArticleDOI
10 Oct 1996-Nature
TL;DR: Oocyte growth and zona pellucida formation proceed normally, but other aspects of oocyte differentiation are compromised, and GDF-9 is the first oocyte-derived growth factor required for somatic cell function in vivo.
Abstract: Growth factors synthesized by ovarian somatic cells directly affect oocyte growth and function, but it is unclear whether oocyte-secreted factors play a reciprocal role in modulating somatic cell functions in vivo. During the functional analysis of members of the transforming growth factor-beta superfamily in mouse development, we have uncovered a new family member, growth differentiation factor-9 (GDF-9), which is required for ovarian folliculogenesis. GDF-9 messenger RNA is synthesized only in the oocyte from the primary one-layer follicle stage until after ovulation. Here we analyse ovaries from GDF-9-deficient female mice and demonstrate that primordial and primary one-layer follicles can be formed, but there is a block in follicular development beyond the primary one-layer follicle stage which leads to complete infertility. Oocyte growth and zona pellucida formation proceed normally, but other aspects of oocyte differentiation are compromised. Thus, GDF-9 is the first oocyte-derived growth factor required for somatic cell function in vivo.

1,541 citations


"Regulation of germ cell development..." refers background in this paper

  • ...In prepuberal mice, a large fraction of the growing oocytes fail to achieve meiotic competence and oocytes of both prepuberal and adult mice show specific ultrastructural abnormalities, including an apparently disorganized cytoskeleton.(56,109) These abnormalities cannot be attributed to an autocrine effect of GDF9 on the oocyte, because deletion of Smad4 within the oocyte has no phenotypic effect....

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  • ...Female mice lacking Gdf9 are anovulatory and sterile.(109) The granulosa cells fail to proliferate normally and do not generate more than a single layer around the growing oocyte....

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  • ...The follicles of Gdf9 females also fail to acquire a thecal layer.(21,109,112) These cells arise from Focus Article wires....

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Book ChapterDOI
TL;DR: This chapter discusses the development of follicles in the mammalian ovary, a complex, functional miniature organ arises from the handful of cells that constitute a simple primordial follicle, a structure so small that it is invisible at the lower magnifications of a light microscope.
Abstract: Publisher Summary This chapter discusses the development of follicles in the mammalian ovary. The unresolved issues in follicular development are focused. Folliculogenesis culminates in the production of fully ripe, preovulatory follicles visible to the naked eye as large bulges on the surface of the ovary. Each ripe follicle contains thousands of highly differentiated cells. This complex, functional miniature organ arises from the handful of cells that constitute a simple primordial follicle, a structure so small that it is invisible at the lower magnifications of a light microscope. All regulatory influences can only permit or prevent cells from completing the full maturation process; they cannot change the course of differentiation. A plethora of modulating influences act as permissive inducers, impeding or propelling the committed follicular cells through the process of clonal expansion. As each follicle progresses through its program of limited clonal expansion and maturation, its cells proliferate more and more rapidly. With every passing generation, the proliferative potential of the granulosa and theca cells continues to diminish, while the state of maturation increases.

1,239 citations


"Regulation of germ cell development..." refers background in this paper

  • ...Upon entry into the growth phase, the squamous granulosa cells that characterize the primordial follicle become cuboidal in shape and begin to proliferate mitotically so that they continue to fully cover the expanding surface of the growing oocyte.(19,20) These follicles, now termed primary, are delimited by a basement membrane that lies apposed to the basal side of the granulosa cells....

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Journal ArticleDOI
TL;DR: The similarities and differences between these two classes of vesicle are reviewed, suggesting that, despite their considerable differences, the functions of ectosomes may be largely analogous to those of exosomes.

1,004 citations

Journal ArticleDOI
TL;DR: A new perspective on oocyte-CC interactions is improving knowledge of the processes regulating oocyte quality, which is likely to have a number of applications, including improving the efficiency of clinical IVM and thereby providing new options for the treatment of infertility.
Abstract: Oocyte quality is a key limiting factor in female fertility, yet we have a poor understanding of what constitutes oocyte quality or the mechanisms governing it. The ovarian follicular microenvironment and maternal signals, mediated primarily through granulosa cells (GCs) and cumulus cells (CCs), are responsible for nurturing oocyte growth, development and the gradual acquisition of oocyte developmental competence. However, oocyte-GC/CC communication is bidirectional with the oocyte secreting potent growth factors that act locally to direct the differentiation and function of CCs. Two important oocyte-secreted factors (OSFs) are growth-differentiation factor 9 and bone morphogenetic protein 15, which activate signaling pathways in CCs to regulate key genes and cellular processes required for CC differentiation and for CCs to maintain their distinctive phenotype. Hence, oocytes appear to tightly control their neighboring somatic cells, directing them to perform functions required for appropriate development of the oocyte. This oocyte-CC regulatory loop and the capacity of oocytes to regulate their own microenvironment by OSFs may constitute important components of oocyte quality. In support of this notion, it has recently been demonstrated that supplementing oocyte in vitro maturation (IVM) media with exogenous OSFs improves oocyte developmental potential, as evidenced by enhanced pre- and post-implantation embryo development. This new perspective on oocyte-CC interactions is improving our knowledge of the processes regulating oocyte quality, which is likely to have a number of applications, including improving the efficiency of clinical IVM and thereby providing new options for the treatment of infertility.

836 citations


"Regulation of germ cell development..." refers background in this paper

  • ...Factors secreted by the oocyte do, however, regulate the differentiation of the granulosa cells and even the thecal calls.(21,87,101) GDF9 and bone morphogenetic protein (BMP) 15 are closely related members of the transforming growth factor (TGF) β superfamily....

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Journal ArticleDOI
11 Jul 2003-Science
TL;DR: It is shown that Foxo3a–/– female mice exhibit a distinctive ovarian phenotype of global follicular activation leading to oocyte death, early depletion of functional ovarian follicles, and secondary infertility, raising the possibility that accelerated follicular initiation plays a role in premature ovarian failure, a common cause of infertility and premature aging in women.
Abstract: Foxo transcription factors have been implicated in diverse biological processes, including metabolism, cellular stress responses, and aging Here, we show that Foxo3a-/- female mice exhibit a distinctive ovarian phenotype of global follicular activation leading to oocyte death, early depletion of functional ovarian follicles, and secondary infertility Foxo3a thus functions at the earliest stages of follicular growth as a suppressor of follicular activation In addition to providing a molecular entry point for studying the regulation of follicular growth, these results raise the possibility that accelerated follicular initiation plays a role in premature ovarian failure, a common cause of infertility and premature aging in women

812 citations


"Regulation of germ cell development..." refers background in this paper

  • ...Finally, the transcription factor, FOXO3, translocates from the nucleus to the cytoplasm at an early stage of growth and genetic deletion of Foxo3 cause most oocytes in primordial follicles to begin to grow.(59,71) Similarly, deletion of the oocyte-specific transcription factor Sohlh2 or oocyte-specific deletion of transcription factor Lhx8 also trigger initiation of oocyte growth, apparently independently of signals from the granulosa cells....

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