Intraovarian factors play important roles in coordinating germ cell and somatic cell growth in the ovary. Prior to the onset of gonadotropin stimulation and reproductive cyclicity, follicle development is dependent upon locally produced growth factors, such as the transforming growth factor beta family members inhibin, activin, and GDF9. In the absence of inhibin in prepubertal mice (Inha−/−), there are marked alterations in preantral follicle growth, but no evidence of ovarian tumors characteristic of adult Inha-null mice. To ascertain the contribution of GDF9 to the Inha-null phenotype, we analyzed folliculogenesis in postnatal Inha Gdf9 double knockout mice. Deletion of Gdf9 from Inha−/− rescues the initial growth defects found at early follicle stages in Inha−/− ovaries, but surprisingly enhances the onset of pretumor lesions. The normalization of growth dynamics between granulosa cells and oocytes of Inha Gdf9 double knockout mice is also accompanied by a reduction in levels of the activin/inhibin beta B subunit, Inhbb, which is upregulated in Inha−/− ovaries. However, at later ages, Inha Gdf9 double knockout ovaries are similar to Inha−/− ovaries, and show upregulation of the activin/inhibin subunits and downregulation of the growth factor, kit ligand, thus resulting in a local environment that is growth-promoting for granulosa cells but growth-inhibitory for oocytes. These data suggest a sequential mechanism of action initiated by GDF9 in the Inha knockout mouse that promotes defective folliculogenesis. These studies thus provide a novel role for GDF9 in causing reproductive defects and suppressing tumor initiation in the Inha−/− mouse model.
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Vol. 88 • No. 4