Адам GDF9 гені: Ооцит өсуі мен аналық сүектер дамуындағы рөлі

Protein coding gene in the species Homo sapiens

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

Growth differentiation factor 9 (GDF9) is an oocyte derived growth factor in the transforming growth factor β (TGF β) superfamily. It is highly expressed in the oocyte and has a pivotal influence on the surrounding somatic cells, particularly granulosa, cumulus and theca cells. GDF9 is essential for the overall process of folliculogenesis, oogenesis and ovulation and thus plays a major role in female fertility. Ligand receptor activation allows the downstream phosphorylation and activation of SMAD proteins. 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. 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. In vitro exposure of mammalian ovarian tissue to GDF9 promotes primary follicle progression. GDF9 stimulates growth of preantral follicles by preventing granulosa cell apoptosis. This may occur through increased follicle stimulating hormone (FSH) receptor expression or be a result of post receptor signaling. 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.

Typical of later stages of follicle development is the appearance of cumulus cells. GDF9 causes the expansion of cumulus cells, a characteristic process in normal follicular development. 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.

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. 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.

GDF9 mutations are present in women with premature ovarian failure, in addition to mothers of dizygotic twins. 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.

PCOS accounts for approximately 90% of anovulation infertility, affecting 5 10% of woman of reproductive age. In women with PCOS, GDF9 mRNA is decreased in all stages of follicular development compared to women without PCOS. Women with PCOS have considerably lower expression of GDF9 in primordial, primary and secondary stages of folliculogenesis. The silencing of ‘’Bmp15’’ in mice results in partial fertility but normal histological appearance of the ovary. GDF9 plays an important role in the development of primary follicles in the ovary. It has a critical role in granulosa cell and theca cell growth, as well as in differentiation and maturation of the oocyte. GDF9 has been connected to differences in ovulation rate and in premature cessation of ovary function, 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).