Disease relevance of Gdf9

• Although targeted gene disruption of GDF-9, an oocyte derived growth factor, leads to an arrest of folliculogenesis and causes infertility in female mice, little is known on the expression of GDF-9 protein in the ovary [1].
• The objective of this study was to examine the effects of galactose on initiation of folliculogenesis in the peripubertal interval and the connection between galactose toxicity and GDF-9 expression in the ovary [2].

High impact information on Gdf9

• This BMP-6 activity resembles BMP-15 but differs from GDF-9 activities [3].
• In cultured rat granulosa cells from early antral follicles, treatment with GDF-9 stimulated the CAGA-luciferase reporter activity and induced the phosphorylation of Smad3 [4].
• In conclusion, although GDF-9 binds to the BMP-activated type II receptor, its downstream actions are mediated by the type I receptor, ALK5, and the Smad2 and Smad3 proteins [4].
• Using P19 cells, we now report that GDF-9 treatment stimulated the CAGA-luciferase reporter known to be responsive to TGF-beta mediated by the type I receptor, activin receptor-like kinase (ALK)5 [4].
• Furthermore, transfection with small interfering RNA for ALK5 or overexpression of the inhibitory Smad7 resulted in dose-dependent suppression of GDF-9 actions [4].

Biological context of Gdf9

• Northern blot analyses of the ontogeny of GDF-9 gene expression in postnatal rat ovaries showed that the GDF-9 transcript levels are clearly increased on the second postnatal day concomitant with the appearance of primary follicles [1].
• The synergistic stimulation of inhibin secretion by the paracrine hormone GDF-9 and the endocrine hormone FSH could play an important role in the feedback regulation of FSH release, thus leading to the modulation of follicle maturation and ovulation [5].
• The present study suggests that a high galactose diet inhibits follicular development, possibly through down-regulation of GDF-9 in the rat ovary, implying that GDF-9 may be involved in galactose-related ovarian toxicity [2].
• Porcine GDF-9 has open reading frame (ORF) homologies of 81.4%, 84.6%, 84.2%, 72.7% and 72.6% with its human, bovine, ovine, rat and mouse counterparts respectively [6].
• MAIN OUTCOME MEASURE(S): Estrous cyclicity, pituitary and peripheral FSH and LH, serum estrogen and progesterone, ovarian histology, and immunocytochemistry for localizing growth differentiation factor-9 and activin receptors-I [7].

Anatomical context of Gdf9

• Immunohistochemical staining of ovarian sections indicated the localization of GDF-9 protein in the oocyte of primary, secondary and preantral follicles, whereas immunoblotting demonstrated the secretion of GDF-9 by mammalian cells transfected with GDF-9 cDNAs [8].
• Recombinant growth differentiation factor-9 (GDF-9) enhances growth and differentiation of cultured early ovarian follicles [8].
• Murine GDF9 stimulated thymidine incorporation by granulosa cells whereas oGDF9 and oBMP15 alone had no effect [9].
• Therefore, GDF-9 mRNA expression in rodents is not exclusive to the ovary, but includes the testis and hypothalamus [10].
• GDF-9 mRNA was detected in mouse and rat ovary, testis, and hypothalamus by Northern blot and RT-PCR analyses [10].

Associations of Gdf9 with chemical compounds

• The effects of murine (m) and ovine (o) GDF9 as well as oBMP15, alone or together, on 3H-thymidine uptake and progesterone and inhibin production by granulosa cells from rats were determined [9].
• Similar to other TGF-beta family ligands, GDF-9 likely initiates signaling mediated by type I and type II receptors with serine/threonine kinase activity, followed by the phosphorylation of intracellular transcription factors named Smads [4].
• Granulosa cells from small antral follicles of diethylstilbestrol-primed immature rats were cultured with FSH in the presence or absence of increasing concentrations of GDF-9 [5].
• Growth differentiation factor-9 stimulates rat theca-interstitial cell androgen biosynthesis [11].
• Although GDF-9 treatment alone stimulated basal steroidogenesis in granulosa cells, cotreatment with GDF-9 suppressed FSH-stimulated progesterone and estradiol production [12].

Regulatory relationships of Gdf9

• Growth differentiation factor-9 stimulates inhibin production and activates Smad2 in cultured rat granulosa cells [5].
• In addition, GDF-9 cotreatment attentuated FSH-induced LH receptor formation [12].

Other interactions of Gdf9

• After overexpression of ALK5, with or without exogenous Smad3, the Cos7 cells gained GDF-9 responsiveness based on the CAGA-luciferase reporter assay [4].
• Growth differentiation factor-9 (GDF-9) and activin A, at the same concentration as TGFbeta1 (10 ng/ml), stimulated LOX mRNA and activity within 6 h, although overall expression was higher at 48 h [13].
• Treatment with FSH or GDF-9 resulted in increased inhibin-alpha gene promoter activity, and combined treatment with both led to synergistic increases [5].

Analytical, diagnostic and therapeutic context of Gdf9

• The localization of GDF-9 mRNA specifically in oocytes of the mouse ovary was confirmed by in situ hybridization histochemistry [10].
• Ovarian follicles were counted by morphometric analysis and GDF-9 expression was investigated by immunohistochemistry and immunoblot assay [2].
• Molecular cloning of porcine growth differentiation factor 9 (GDF-9) cDNA and its role in early folliculogenesis: direct ovarian injection of GDF-9 gene fragments promotes early folliculogenesis [6].

References