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The Magic of the Ovary: How does GDF9 affect every step of egg development?
In the female reproductive process, the health of the ovaries is closely related to the development of eggs. Growth and differentiation factor 9 (GDF9) is a protein synthesized by the egg and has a critical influence on the egg and its surrounding supporting cells. GDF9 belongs to the transforming growth factor beta (TGF-β) superfamily and is mainly expressed by cells in eggs. Notably, GDF9 is essential for folliculogenesis and egg development, and even plays a major role in female fertility.
GDF9 signaling pathway
GDF9 exerts its effects by binding to two receptors on cells surrounding the egg, mainly bone morphogenetic protein receptor type 2 (BMPRII) and TGF-β receptor type 1 (ALK5). Activation of these receptors can trigger the phosphorylation of downstream SMAD proteins, which are transcription factors that regulate gene expression.
GDF9 specifically activates SMAD2 and SMAD3. These proteins bind to SMAD4 and then enter the nucleus to regulate gene expression.
Role in folliculogenesis
Early follicle development
In many mammals, GDF9 is critical for the development of early follicles, where it promotes the proliferation and differentiation of granulosa cells. Deletion of GDF9 results in reduced ovarian size, arrested follicle development at the primary stage, and lack of corpus luteum formation.
The deficiency of GDF9 will also lead to the up-regulation of inhibin. Normally expressed GDF9 can down-regulate inhibin, thereby promoting the further development of follicles.
In addition, in the laboratory, GDF9 treatment of mammalian ovarian tissue promoted the development of primary follicles.
Late follicle development
GDF9 also promotes the expansion of granulosa cells surrounding granulosa cells during late stages of follicle development. This process is a feature of normal follicular development. GDF9 induces the expansion of cumulus cells and does this by altering enzymes within granulosa cells.
Silencing GDF9 signaling results in failure to achieve granulosa cell expansion, demonstrating its importance in late folliculogenesis.
Role in egg production and ovulation
Ovogenesis
Lack of GDF9 not only causes ovarian abnormalities, but also affects egg development, resulting in impaired formation of its cage structure and greatly reduced egg ability in meiosis.
Ovulation process
GDF9 is required in the stages leading up to the peak of luteinizing hormone (LH), a process that is an important component of ovulation. GDF9 supports the metabolic function of granulosa cells, thereby supporting estrogen production. In addition, GDF9 also promotes progesterone production in preovulatory follicles, which is critical for early embryonic development.
GDF9 expression changes in humans
GDF9 mutation
GDF9 mutations have been found in some women with early ovarian failure. These mutations may affect the rate of ovulation and therefore fertility.
Mutations in GDF9 are linked to polycystic ovary syndrome (PCOS), one of the leading causes of anovulatory infertility in women.
Association with polycystic ovary syndrome
In PCOS patients, GDF9 expression is significantly reduced at all stages of follicle development, and this change may lead to reduced fertility, although the specific mechanism is not yet clear.
Synergy
The synergy between GDF9 and bone morphogenetic protein 15 (BMP15) is critical for folliculogenesis. The two proteins work together to promote granulosa cell proliferation, but their effects vary between species.
In addition, the cooperation of GDF9 and BMP15 affects the ability to release eggs, showing the close influence of these factors on ovarian function.
In summary, GDF9 plays an extremely important role in the female reproductive system. From folliculogenesis, egg development to ovulation, every step is affected by GDF9. So, should we pay more attention to the potential impact of this factor on women’s reproductive health?
