Growth differentiation factor-9

Last updated
GDF9
Identifiers
Aliases GDF9 , entrez:2661, growth differentiation factor 9, POF14
External IDs OMIM: 601918 MGI: 95692 HomoloGene: 3851 GeneCards: GDF9
Orthologs
SpeciesHumanMouse
Entrez

2661

14566

Ensembl

ENSG00000164404

ENSMUSG00000018238

UniProt

O60383

Q07105

RefSeq (mRNA)

NM_008110

RefSeq (protein)

NP_032136

Location (UCSC) Chr 5: 132.86 – 132.87 Mb Chr 11: 53.32 – 53.33 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Growth/differentiation factor 9 is a protein that in humans is encoded by the GDF9 gene. [5] [6]

Contents

Growth factors synthesized by ovarian somatic cells directly affect oocyte growth and function. Growth differentiation factor-9 (GDF9) is expressed in oocytes and is thought to be required for ovarian folliculogenesis. GDF9 is a member of the transforming growth factor-beta (TGFβ) superfamily. [6]

Growth Differentiation Factor 9 (GDF9)

Growth differentiation factor 9 (GDF9) is an oocyte derived growth factor in the transforming growth factor β (TGF-β) superfamily. [7] It is highly expressed in the oocyte and has a pivotal influence on the surrounding somatic cells, particularly granulosa, cumulus and theca cells. [7] Paracrine interactions between the developing oocyte and its surrounding follicular cells is essential for the correct progression of both the follicle and the oocyte. [8] GDF9 is essential for the overall process of folliculogenesis, oogenesis and ovulation and thus plays a major role in female fertility. [8]

Signaling Pathway

GDF9 acts through two receptors on the cells surrounding the oocyte, it binds to bone morphogenic protein receptor 2 (BMPRII) and downstream to this utilizes the TGF-β receptor type 1 (ALK5). [9] Ligand receptor activation allows the downstream phosphorylation and activation of SMAD proteins. [8] SMAD proteins are transcription factors found in vertebrates, insects and nematodes, and are the intercellular substrates of all TGF-β molecules. [10] GDF9 specifically activates SMAD2 and SMAD3 which form a complex with SMAD4, a common partner of all SMAD proteins, that is then able to translocate to the nucleus to regulate gene expression. [9]

Role in Folliculogenesis

Early Follicle Development

In many mammalian species GDF9 is essential for early follicular development through its direct action on the granulosa cells allowing proliferation and differentiation [7] The deletion of ‘’Gdf9’’ results in decreased ovary size, halted follicular development at the stage of the primary follicle and the absence of any corpus lutea. [11] The proliferative ability of granulosa cells is significantly reduced whereby no more than a single layer of granulosa cells is able to surround and thus support the developing oocyte. [7] Any somatic cell formation after the primary layer is atypical and asymmetrical. [11] Normally the follicle becomes atretic and degenerates although this does not occur emphasizing the abnormality of these supporting cells. [11] GDF9 deficiency is further linked with the up regulation of inhibin. [7] The normal expression of GDF9 allows the downregulation of inhibin a and thus promotes the ability of the follicle to progress past the primary stage of development. [12]

In vitro exposure of mammalian ovarian tissue to GDF9 promotes primary follicle progression. [13] [14] GDF9 stimulates growth of preantral follicles by preventing granulosa cell apoptosis. [15] This may occur through increased follicle stimulating hormone (FSH) receptor expression or be a result of post-receptor signaling. [7]

Some sheep breeds show a range of fertility phenotypes due to eight single nucleotide polymorphisms (SNP) across the coding region of GDF9. [16] A SNP in the Gdf9 gene resulting in a non conservative amino acid change was identified, whereby ewes homozygous for the SNP were infertile and completely lacked any follicle growth. [17]

Late Follicle Development

Typical of later stages of follicle development is the appearance of cumulus cells. [18] GDF9 causes the expansion of cumulus cells, a characteristic process in normal follicular development. [8] GDF9 induces hyaluronanic synthase 2 (Has2) and suppresses urokinase plasminogen activator (uPA) mRNA synthesis in granulosa cells. [18] This allows an extracellular matrix rich in hyaluronic acid, allowing the expansion of cumulus cells. [19] Silencing of GDF9 expression results in the absence of cumulus cell expansion, this highlights the integral role of GDF9 signaling in altering granulosa cell enzymes and therefore allowing cumulus cell expansion in late stages of folliculogenesis. [18] [20]

Role in Oogenesis and Ovulation

Role in Oogenesis

A lack of GDF9 causes pathophysiological alterations in the oocyte itself in addition to severe follicular abnormality. Oocytes reach normal size and form a zona pellucida although organelles become clustered and cortical granules do not form. [11] In GDF9 deficient oocytes the meiotic ability is significantly altered, where less than half will proceed metaphase 1 or 2 and a large percentage of oocytes have abnormal germinal vesicle breakdown. [11] As cumulus cells surround the oocyte during development and remain with the oocyte once it is ovulated, GDF9 expression in cumulus cells is important in allowing an ideal oocyte microenvironment. [18] The altered phenotype observed in GDF9 deficient oocytes likely results from the lack off somatic cell input in later stages of folliculogenesis. [11]

Role in Ovulation

GDF9 is required just prior to the surge of luteinizing hormone (LH), a key event responsible for ovulation. [7] Prior to the LH surge, GDF9 supports the metabolic function of cumulus cells, allowing glycolysis and cholesterol biosynthesis. [21] Cholesterol is a precursor of many essential steroid hormones such as progesterone. Progesterone levels rise significantly post ovulation to support the early stages of embryogenesis. [7] In preovulatory follicles, GDF9 promotes the production of progesterone via the stimulation of the prostaglandin- EP2 receptor signaling pathway. [22]

Altered GDF9 Expression in Humans

Mutations in GDF9

GDF9 mutations are present in women with premature ovarian failure, in addition to mothers of dizygotic twins. [7] [23] Three particular missense mutations GDF9 P103S, GDF9 P374L and GDF9 R454C have been found, although GDF9 P103S is present in women with dizygotic twins as well as women with premature ovarian failure. [7] Given the same mutation is linked with a poly ovulatory phenotype and the failure of ovulation, these mutations are thought to alter the rate of ovulation, rather than specifically increasing or decreasing the rate. [7] Most of these mutations are located in the pro-region of the gene that encodes GDF9, an area essential for the dimerization and hence activation of the encoded protein. [24] [25]

PCOS accounts for approximately 90% of anovulation infertility, affecting 5-10% of woman of reproductive age. [26] In women with PCOS, GDF9 mRNA is decreased in all stages of follicular development compared to women without PCOS. [7] In particular, levels of GDF9 increase as the follicle develops from primordial stages to more mature stages. [27] Women with PCOS have considerably lower expression of GDF9 in primordial, primary and secondary stages of folliculogenesis. [27] GDF9 expression is not only reduced in women with PCOS but also delayed. [27] Despite these facts the exact link of GDF9 with PCOS is not well established. [7]

Synergistic Interaction

Bone morphogenic protein 15 (BMP15) is highly expressed in the oocyte and the surrounding follicular cells contributing greatly to folliculogenesis and oogenesis. [7] Like GDF9, BMP15 belongs to the TGF-β superfamily. [7] Differences in the synergistic action of BMP15 and GDF9 appear to be species dependent. [7] BMP15 and GDF9 act in an additive manner to increase mitotic proliferation in sheep granulosa cells, although the same effect is not observed in bovine granulosa cells. [28] The silencing of ‘’Bmp15’’ in mice results in partial fertility but normal histological appearance of the ovary. [23] Although, when this is combined with the silencing of one allele of ‘’Gdf9’’, mice are completely infertile due to insufficient folliculogenesis and altered cumulus cell morphology. [23] Mice with this genome also fail to release oocytes resulting in trapped oocytes in the corpus lutea. [23] This phenotype is absent in ‘’Gdf9’’ silenced mice and only present a small population of ‘’Bmp15’’ silenced mice. [23] This reveals the synergistic relationship of GDF9 and BMP15 whereby the silencing of both genes results in more severe outcome then either of the genes alone. It is thought that any co operative effects of GDF9 and BMP15 are modulated through the BMPRII receptor. [29]

GDF9 plays an important role in the development of primary follicles in the ovary. [30] It has a critical role in granulosa cell and theca cell growth, as well as in differentiation and maturation of the oocyte. [13] [31]

GDF9 has been connected to differences in ovulation rate [32] [33] and in premature cessation of ovary function, [34] therefore has a significant role in fertility.

The cell surface receptor through which GDF9 generates a signal is the bone morphogenetic protein type II receptor (BMPR2). [35] [36]

Related Research Articles

Germ cell Gamete-producing cell

A germ cell is any biological cell that gives rise to the gametes of an organism that reproduces sexually. In many animals, the germ cells originate in the primitive streak and migrate via the gut of an embryo to the developing gonads. There, they undergo meiosis, followed by cellular differentiation into mature gametes, either eggs or sperm. Unlike animals, plants do not have germ cells designated in early development. Instead, germ cells can arise from somatic cells in the adult, such as the floral meristem of flowering plants.

Oogenesis The process of the production of egg cells

Oogenesis, ovogenesis, or oögenesis is the differentiation of the ovum into a cell competent to further develop when fertilized. It is developed from the primary oocyte by maturation. Oogenesis is initiated in the embryonic stage.

Ovarian follicle Structure containing a single egg cell

An ovarian follicle is a roughly spheroid cellular aggregation set found in the ovaries. It secretes hormones that influence stages of the menstrual cycle. At the time of puberty, women have approximately 200,000 to 300,000 follicles, each with the potential to release an egg cell (ovum) at ovulation for fertilization. These eggs are developed once every menstrual cycle with around 450-500 being ovulated during a woman's reproductive lifetime.

Granulosa cell

A granulosa cell or follicular cell is a somatic cell of the sex cord that is closely associated with the developing female gamete in the ovary of mammals.

Anti-Müllerian hormone Mammalian protein found in Homo sapiens

Anti-Müllerian hormone (AMH), also known as Müllerian-inhibiting hormone (MIH), is a glycoprotein hormone structurally related to inhibin and activin from the transforming growth factor beta superfamily, whose key roles are in growth differentiation and folliculogenesis. In humans, it is encoded by the AMH gene, on chromosome 19p13.3, while its receptor is encoded by the AMHR2 gene on chromosome 12.

Folliculogenesis Process of maturation of primordial follicles

In biology, folliculogenesis is the maturation of the ovarian follicle, a densely packed shell of somatic cells that contains an immature oocyte. Folliculogenesis describes the progression of a number of small primordial follicles into large preovulatory follicles that occurs in part during the menstrual cycle.

Follicular phase Phase of the estrous or menstrual cycle

The follicular phase, also known as the preovulatory phase or proliferative phase, is the phase of the estrous cycle during which follicles in the ovary mature from primary follicle to a fully mature graafian follicle. It ends with ovulation. The main hormones controlling this stage are secretion of gonadotropin-releasing hormones, which are follicle-stimulating hormones and luteinising hormones. They are released by pulsatile secretion. The duration of the follicular phase can differ depending on the length of the menstrual cycle, while the luteal phase is usually stable, does not really change and lasts 14 days.

Follicular atresia is the breakdown of the ovarian follicles, which consist of an oocyte surrounded by granulosa cells and internal and external theca cells. It occurs continually throughout a woman’s life, as they are born with millions of follicles but will only ovulate around 400 times in their lifetime. Typically around 20 follicles mature each month but only a single follicle is ovulated; the follicle from which the oocyte was released becomes the corpus luteum. The rest undergo atresia.

Bone morphogenetic protein 4 Gene of the species Homo sapiens

Bone morphogenetic protein 4 is a protein that in humans is encoded by BMP4 gene. BMP4 is found on chromosome 14q22-q23.

Bone morphogenetic protein 15 Protein-coding gene in the species Homo sapiens

Bone morphogenetic protein 15 (BMP-15) is a protein that in humans is encoded by the BMP15 gene. It is involved in folliculogenesis, the process in which primordial follicles develop into pre-ovulatory follicles.

Follistatin Mammalian protein found in Homo sapiens

Follistatin also known as activin-binding protein is a protein that in humans is encoded by the FST gene. Follistatin is an autocrine glycoprotein that is expressed in nearly all tissues of higher animals.

BMPR2

Bone morphogenetic protein receptor type II or BMPR2 is a serine/threonine receptor kinase. It binds Bone morphogenetic proteins, members of the TGF beta superfamily of ligands, which are involved in paracrine signalling. BMPs are involved in a host of cellular functions including osteogenesis, cell growth and cell differentiation. Signaling in the BMP pathway begins with the binding of a BMP to the type II receptor. This causes the recruitment of a BMP type I receptor, which it phosphorylates. The Type I receptor phosphorylates an R-SMAD a transcriptional regulator.

Growth differentiation factors (GDFs) are a subfamily of proteins belonging to the transforming growth factor beta superfamily that have functions predominantly in development.

GDF2

Growth differentiation factor 2 (GDF2) also known as bone morphogenetic protein (BMP)-9 is a protein that in humans is encoded by the GDF2 gene. GDF2 belongs to the transforming growth factor beta superfamily.

GDF6 Protein-coding gene in the species Homo sapiens

Growth differentiation factor 6 (GDF6) is a protein that in humans is encoded by the GDF6 gene.

Antral follicle

An antral follicle, also known as Graafian follicle and tertiary follicle, is an ovarian follicle during a certain latter stage of folliculogenesis.

Ovarian follicle activation can be defined as primordial follicles in the ovary moving from a quiescent (inactive) to a growing phase. The primordial follicle in the ovary is what makes up the “pool” of follicles that will be induced to enter growth and developmental changes that change them into pre-ovulatory follicles, ready to be released during ovulation. The process of development from a primordial follicle to a pre-ovulatory follicle is called folliculogenesis.

Gonadotropin surge-attenuating factor (GnSAF) is a nonsteroidal ovarian hormone produced by the granulosa cells of small antral ovarian follicles in females. GnSAF is involved in regulating the secretion of luteinizing hormone (LH) from the anterior pituitary and the ovarian cycle. During the early to mid-follicular phase of the ovarian cycle, GnSAF acts on the anterior pituitary to attenuate LH release, limiting the secretion of LH to only basal levels. At the transition between follicular and luteal phase, GnSAF bioactivity declines sufficiently to permit LH secretion above basal levels, resulting in the mid-cycle LH surge that initiates ovulation. In normally ovulating women, the LH surge only occurs when the oocyte is mature and ready for extrusion. GnSAF bioactivity is responsible for the synchronised, biphasic nature of LH secretion.

Resumption of meiosis occurs as a part of oocyte meiosis after meiotic arrest has occurred. In females, meiosis of an oocyte begins during embryogenesis and will be completed after puberty. A primordial follicle will arrest, allowing the follicle to grow in size and mature. Resumption of meiosis will resume following an ovulatory surge (ovulation) of luteinising hormone (LH).

Jennifer Lee Juengel is an animal health researcher in New Zealand. She has been a Fellow of the Royal Society Te Apārangi since 2016.

References

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  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  16. ↑ Hanrahan, J. (2003). Mutations in the Genes for Oocyte-Derived Growth Factors GDF9 and BMP15 Are Associated with Both Increased Ovulation Rate and Sterility in Cambridge and Belclare Sheep (Ovis aries). Biology of Reproduction, 70(4), pp.900-909
  17. ↑ Nicol, L., Bishop, S., Pong-Wong, R., Bendixen, C., Holm, L., Rhind, S. and McNeilly, A. (2009). Homozygosity for a single base-pair mutation in the oocyte-specific GDF9 gene results in sterility in Thoka sheep. Reproduction, 138(6), pp.921-933
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  19. ↑ Zhao, H., Qin, Y., Kovanci, E., Simpson, J., Chen, Z. and Rajkovic, A. (2007). Analyses of GDF9 mutation in 100 Chinese women with premature ovarian failure. Fertility and Sterility, 88(5), pp.1474-1476
  20. ↑ Gui, L. (2005). RNA Interference Evidence That Growth Differentiation Factor-9 Mediates Oocyte Regulation of Cumulus Expansion in Mice. Biology of Reproduction, 72(1), pp.195-199
  21. ↑ Sugiura, K., Pendola, F. and Eppig, J. (2005). Oocyte control of metabolic cooperativity between oocytes and companion granulosa cells: energy metabolism. Developmental Biology, 279(1), pp.20-30
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  24. ↑ Laissue, P. (2006). Mutations and sequence variants in GDF9 and BMP15 in patients with premature ovarian failure. European Journal of Endocrinology, 154(5), pp.739-744
  25. ↑ Shimasaki, S., Moore, R., Otsuka, F. and Erickson, G. (2004). The Bone Morphogenetic Protein System In Mammalian Reproduction. Endocrine Reviews, 25(1), pp.72-101
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  28. ↑ McNatty, K., Juengel, J., Reader, K., Lun, S., Myllymaa, S., Lawrence, S., Western, A., Meerasahib, M., Mottershead, D., Groome, N., Ritvos, O. and Laitinen, M. (2005). Bone morphogenetic protein 15 and growth differentiation factor 9 co-operate to regulate granulosa cell function in ruminants. Reproduction, 129(4), pp.481-487
  29. ↑ Edwards, S., Reader, K., Lun, S., Western, A., Lawrence, S., McNatty, K. and Juengel, J. (2008). The Cooperative Effect of Growth and Differentiation Factor-9 and Bone Morphogenetic Protein (BMP)-15 on Granulosa Cell Function Is Modulated Primarily through BMP Receptor II. Endocrinology, 149(3), pp.1026-1030
  30. ↑ Juengel J, Bodensteiner K, Heath D, Hudson N, Moeller C, Smith P, Galloway S, Davis G, Sawyer H, McNatty K (2004). "Physiology of GDF9 and BMP15 signalling molecules". Anim Reprod Sci . 82–83: 447–60. doi:10.1016/j.anireprosci.2004.04.021. PMID   15271472.
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  35. ↑ Mazerbourg S, Hsueh A (2006). "Genomic analyses facilitate identification of receptors and signalling pathways for growth differentiation factor 9 and related orphan bone morphogenetic protein/growth differentiation factor ligands". Hum Reprod Update. 12 (4): 373–83. doi: 10.1093/humupd/dml014 . PMID   16603567.
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