Oocyte–somatic cell interactions during follicle development in mammals
TL;DR: Elucidating the nature of oocyte-somatic cell interactions at the various stages of follicle development will have important implications for the understanding of factors regulating folliculogenesis, ovulation rate and fecundity.
About: This article is published in Animal Reproduction Science.The article was published on 2004-07-01. It has received 559 citations till now. The article focuses on the topics: Folliculogenesis & Granulosa cell.
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TL;DR: Advances in the understanding of intraovarian regulatory mechanisms should facilitate the development of new approaches for monitoring and manipulating ovarian function and improving fertility in domesticated livestock, endangered species and man.
Abstract: In recent years, exciting progress has been made towards unravelling the complex intraovarian control mechanisms that, in concert with systemic signals, coordinate the recruitment, selection and growth of follicles from the primordial stage through to ovulation and corpus luteum formation. A plethora of growth factors, many belonging to the transforming growth factor-beta (TGF-beta ) superfamily, are expressed by ovarian somatic cells and oocytes in a developmental, stage-related manner and function as intraovarian regulators of folliculogenesis. Two such factors, bone morphogenetic proteins, BMP-4 and BMP-7, are expressed by ovarian stromal cells and/or theca cells and have recently been implicated as positive regulators of the primordial-to-primary follicle transition. In contrast, evidence indicates a negative role for anti-Mullerian hormone (AMH, also known as Mullerian-inhibiting substance) of pre-granulosa/granulosa cell origin in this key event and subsequent progression to the antral stage. Two other TGF-beta superfamily members, growth and differentiation factor-9 (GDF-9) and BMP-15 (also known as GDF-9B) are expressed in an oocyte-specific manner from a very early stage and play key roles in promoting follicle growth beyond the primary stage; mice with null mutations in the gdf-9 gene or ewes with inactivating mutations in gdf-9 or bmp-15 genes are infertile with follicle development arrested at the primary stage. Studies on later stages of follicle development indicate positive roles for granulosa cell-derived activin, BMP-2, -5 and -6, theca cell-derived BMP-2, -4 and -7 and oocyte-derived BMP-6 in promoting granulosa cell proliferation, follicle survival and prevention of premature luteinization and/or atresia. Concomitantly, activin, TGF-beta and several BMPs may exert paracrine actions on theca cells to attenuate LH-dependent androgen production in small to medium-size antral follicles. Dominant follicle selection in monovular species may depend on differential FSH sensitivity amongst a growing cohort of small antral follicles. Changes in intrafollicular activins, GDF-9, AMH and several BMPs may contribute to this selection process by modulating both FSH- and IGF-dependent signalling pathways in granulosa cells. Activin may also play a positive role in oocyte maturation and acquisition of developmental competence. In addition to its endocrine role to suppress FSH secretion, increased output of inhibin by the selected dominant follicle(s) may upregulate LH-induced androgen secretion that is required to sustain a high level of oestradiol secretion during the pre-ovulatory phase. Advances in our understanding of intraovarian regulatory mechanisms should facilitate the development of new approaches for monitoring and manipulating ovarian function and improving fertility in domesticated livestock, endangered species and man.
1,037 citations
TL;DR: Recent advances on teleost fish oocyte differentiation, maturation and ovulation are highlighted, including those involved in the degeneration and reabsorption of ovarian follicles (atresia).
910 citations
Cites background from "Oocyte–somatic cell interactions du..."
...Two members of the TGF-b family that are expressed in oocytes, growth and differentiation factor 9 (GDF9) and bone morphogenetic factor 15 (BMP15), both of which play important roles in early ovarian follicle growth in mammals (Gilchrist et al., 2004; Juengel et al., 2004; Moore and Shimasaki, 2005), have been implicated in primary ovarian follicle...
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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
Cites background from "Oocyte–somatic cell interactions du..."
...To date, the focus has been almost entirely on members of the TGFb superfamily as constituting the key OSFs (reviews; Vanderhyden et al., 2003; Gilchrist et al., 2004a)....
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...This may account for the fact that the COC is the last compartment of the ovarian follicle to be affected by advanced atresia....
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...…has recently become evident that the oocyte in fact is a central regulator of follicular cell function and thereby plays a critical role in the regulation of oogenesis, ovulation rate and fecundity (reviews; Eppig, 2001; Gilchrist et al., 2004a; McNatty et al., 2004; Gilchrist and Thompson, 2007)....
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...…thymidine uptake as a measure of DNA synthesis, increases in total DNA content from GC cultures and increased numbers of GCs (Vanderhyden et al., 1992; Lanuza et al., 1998; Li et al., 2000; Gilchrist et al., 2001, 2003, 2004b, 2006; Brankin et al., 2003; Glister et al., 2003; Hickey et al., 2005)....
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...The capacity of oocytes to regulate all these GC functions is first acquired by mouse oocytes at around the time of antrum formation, as oocytes reach the end of their growth phase and acquire meiotic competence (reviewed; Gilchrist et al., 2004a)....
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TL;DR: The relevant pathways of glucose metabolism by COCs during in vivo maturation and IVM are discussed, including the relative contribution of the somatic and gamete compartments of the COC to glucose metabolism.
Abstract: The environment that the cumulus oocyte complex (COC) is exposed to during either in vivo or in vitro maturation (IVM) can have profound effects on the success of fertilisation and subsequent embryo development. Glucose is a pivotal metabolite for the COC and is metabolised by glycolysis, the pentose phosphate pathway (PPP), the hexosamine biosynthesis pathway (HBP) and the polyol pathway. Over the course of oocyte maturation, a large proportion of total glucose is metabolised via the glycolytic pathway to provide substrates such as pyruvate for energy production. Glucose is also the substrate for many cellular functions during oocyte maturation, including regulation of nuclear maturation and redox state via the PPP and for the synthesis of substrates of extracellular matrices (cumulus expansion) and O-linked glycosylation (cell signalling) via the HBP. However, the oocyte is susceptible to glucose concentration-dependent perturbations in nuclear and cytoplasmic maturation, leading to poor embryonic development post-fertilisation. For example, glucose concentrations either too high or too low result in precocious resumption of nuclear maturation. This review will discuss the relevant pathways of glucose metabolism by COCs during in vivo maturation and IVM, including the relative contribution of the somatic and gamete compartments of the COC to glucose metabolism. The consequences of exposing COCs to abnormal glucose concentrations will also be examined, either during IVM or by altered maternal environments, such as during hyperglycaemia induced by diabetes and obesity.
404 citations
Cites background from "Oocyte–somatic cell interactions du..."
...Prior to the ovulatory signal, the oocyte is coupled to its cumulus cells through trans-zonal processes, and this intimate physical association facilitates bi-directional communication between the oocyte and the cumulus vestment via gap junctional and paracrine signalling (Gilchrist et al. 2004)....
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...Conversely, oocytesecreted factors allow for cumulus cell differentiation from mural granulosa cells and mucification of the cumulus vestment (Gilchrist et al. 2004)....
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TL;DR: This review focuses on the recent advances in understanding of molecular mechanisms that commence after the gonadotrophin surge and culminate with release of the oocyte.
Abstract: Successful ovulation requires that developmentally competent oocytes are released with appropriate timing from the ovarian follicle. Somatic cells of the follicle sense the ovulatory stimulus and guide resumption of meiosis and release of the oocyte, as well as structural remodelling and luteinization of the follicle. Complex intercellular communication co-ordinates critical stages of oocyte maturation and links this process with release from the follicle. To achieve these outcomes, ovulation is controlled through multiple inputs, including endocrine hormones, immune and metabolic signals, as well as intrafollicular paracrine factors from the theca, mural and cumulus granulosa cells and the oocyte itself. This review focuses on the recent advances in understanding of molecular mechanisms that commence after the gonadotrophin surge and culminate with release of the oocyte. These mechanisms include intracellular signalling, gene regulation and remodelling of tissue structure in each of the distinct ovarian compartments. Most critical ovulatory mediators exert effects through the cumulus cell complex that surrounds and connects with the oocyte. The convergence of ovulatory signals through the cumulus complex co-ordinates the key mechanistic processes that mediate and control oocyte maturation and ovulation.
375 citations
Cites background from "Oocyte–somatic cell interactions du..."
...…belonging to the Tgfb superfamily establish a morphogen gradient that promotes the cumulus cell characteristics including enhanced cell proliferation, and repression of LH-R and PR gene transcription, and progesterone biosynthesis (Eppig et al., 1998; Elvin et al., 1999a; Gilchrist et al., 2004)....
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...Oocyte-secreted factors (OSF) belonging to the Tgfb superfamily establish a morphogen gradient that promotes the cumulus cell characteristics including enhanced cell proliferation, and repression of LH-R and PR gene transcription, and progesterone biosynthesis (Eppig et al., 1998; Elvin et al., 1999a; Gilchrist et al., 2004)....
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...This oocyte-derived activity, originally referred to as cumulus-expansion-enabling factor (CEEF), is secreted by mouse, pig and cow oocytes (Eppig et al., 1993; Singh et al., 1993; Vanderhyden et al., 1993; Gilchrist et al., 2004)....
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References
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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
TL;DR: It is established that BMP15 is essential for female fertility and that natural mutations in an ovary-derived factor can cause both increased ovulation rate and infertility phenotypes in a dosage-sensitive manner.
Abstract: Multiple ovulations are uncommon in humans, cattle and many breeds of sheep. Pituitary gonadotrophins and as yet unidentified ovarian factors precisely regulate follicular development so that, normally, only one follicle is selected to ovulate. The Inverdale (FecXI) sheep, however, carries a naturally occurring X-linked mutation that causes increased ovulation rate and twin and triplet births in heterozygotes (FecXI/FecX+; ref. 1), but primary ovarian failure in homozygotes (FecXI/FecXI; ref. 2). Germ-cell development, formation of the follicle and the earliest stages of follicular growth are normal in FecXI/FecXI sheep, but follicular development beyond the primary stage is impaired3,4. A second family unrelated to the Inverdale sheep also has the same X-linked phenotype5 (Hanna, FecXH). Crossing FecXI with FecXH animals produces FecXI/FecXH infertile females phenotypically indistinguishable from FecXI/FecXI females6. We report here that the FecXI locus maps to an orthologous chromosomal region syntenic to human Xp11.2–11.4, which contains BMP15, encoding bone morphogenetic protein 15 (also known as growth differentiation factor 9B (GDF9B)). Whereas BMP15 is a member of the transforming growth factor β (TGFβ) superfamily and is specifically expressed in oocytes, its function is unknown7,8,9. We show that independent germline point mutations exist in FecXI and FecXH carriers. These findings establish that BMP15 is essential for female fertility and that natural mutations in an ovary-derived factor can cause both increased ovulation rate and infertility phenotypes in a dosage-sensitive manner.
1,050 citations
TL;DR: The existence of an oocyte-granulosa cell regulatory loop, essential for normal follicular differentiation as well as for the production of a oocyte competent to undergo fertilization and embryogenesis, is proposed.
Abstract: A new perspective on ovarian follicular development has emerged over the last decade. Whereas the oocyte was previously considered only a passive recipient of developmental signals from oocyte-associated granulosa cells, it is now clear that communication between oocytes and granulosa cells is bidirectional. A complex interplay of regulatory factors governs the development of both types of cell. This interplay is essential not only for oocyte development but also for follicular development, beginning with the initial assembly of the primordial follicle and continuing throughout ovulation. The existence of an oocyte-granulosa cell regulatory loop, essential for normal follicular differentiation as well as for the production of an oocyte competent to undergo fertilization and embryogenesis, is proposed. Although gonadotrophins are essential for driving the differentiation of granulosa cell phenotypes, within its sphere of influence, the oocyte is probably the dominant factor determining the direction of differentiation and the function of the granulosa cells associated with it.
948 citations
TL;DR: The dosage of intact Bmp15 and Gdf9 alleles directly influences the destiny of the oocyte during folliculogenesis and in the periovulatory period, which has important implications for human fertility control and the maintenance of fertility and normal ovarian physiology.
Abstract: Knockout mouse technology has been used over the last decade to define the essential roles of ovarian-expressed genes and uncover genetic interactions. In particular, we have used this technology to study the function of multiple members of the transforming growth factor-beta superfamily including inhibins, activins, and growth differentiation factor 9 (GDF-9 or Gdf9). Knockout mice lacking GDF-9 are infertile due to a block in folliculogenesis at the primary follicle stage. In addition, recombinant GDF-9 regulates multiple cumulus granulosa cell functions in the periovulatory period including hyaluronic acid synthesis and cumulus expansion. We have also cloned an oocyte-specific homolog of GDF-9 from mice and humans, which is termed bone morphogenetic protein 15 (BMP-15 or Bmp15). To define the function of BMP-15 in mice, we generated embryonic stem cells and knockout mice, which have a null mutation in this X-linked gene. Male chimeric and Bmp15 null mice are normal and fertile. In contrast to Bmp15 null males and Gdf9 knockout females, Bmp15 null females (Bmp15(-/-)) are subfertile and usually have minimal ovarian histopathological defects, but demonstrate decreased ovulation and fertilization rates. To further decipher possible direct or indirect genetic interactions between GDF-9 and BMP-15, we have generated double mutant mice lacking one or both alleles of these related homologs. Double homozygote females (Bmp15(-/-)Gdf9(-/-)) display oocyte loss and cysts and resemble Gdf9(-/-) mutants. In contrast, Bmp15(-/-)Gdf9(+/-) female mice have more severe fertility defects than Bmp15(-/-) females, which appear to be due to abnormalities in ovarian folliculogenesis, cumulus cell physiology, and fertilization. Thus, the dosage of intact Bmp15 and Gdf9 alleles directly influences the destiny of the oocyte during folliculogenesis and in the periovulatory period. These studies have important implications for human fertility control and the maintenance of fertility and normal ovarian physiology.
781 citations
TL;DR: This is the first time that a mutation in the gene for GDF9 has been found that causes increased ovulation rate and infertility in a manner similar to inactivating mutations in BMP15, and shows that GDF 9 is essential for normal folliculogenesis in sheep.
Abstract: Belclare and Cambridge are prolific sheep breeds, the origins of which involved selecting ewes with exceptionally high litter size records from commercial flocks. The variation in ovulation rate in both breeds is consistent with segregation of a gene (or genes) with a large effect on this trait. Sterile ewes, due to a failure of normal ovarian follicle development, occur in both breeds. New naturally occurring mutations in genes for the oocyte-derived growth factors growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) are described. These mutations are associated with increased ovulation rate in heterozygous carriers and sterility in homozygous carriers in both breeds. This is the first time that a mutation in the gene for GDF9 has been found that causes increased ovulation rate and infertility in a manner similar to inactivating mutations in BMP15, and shows that GDF9 is essential for normal folliculogenesis in sheep. Furthermore, it is shown, for the first time in any species, that individuals with mutations in both GDF9 and BMP15 have a greater ovulation rate than sheep with either of the mutations separately.
745 citations