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Interrelationship of Growth Differentiation Factor 9 and Inhibin in Early Folliculogenesis and Ovarian Tumorigenesis in Mice

Departments of Pathology (X.W., L.C., C.A.B., C.Y., M.M.M.), Molecular and Cellular Biology (M.M.M.), and Molecular and Human Genetics (M.M.M.), Baylor College of Medicine, Houston, Texas 77030

Address all correspondence and requests for reprints to: Martin M. Matzuk, M.D., Ph.D, The Stuart A. Wallace Chair, Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030. E-mail: mmatzuk{at}bcm.tmc.edu.

To investigate the interrelationship of inhibin and growth differentiation factor 9 (GDF9) during early folliculogenesis, we generated mice lacking both inhibin and GDF9. Our findings on these Inha Gdf9 double-mutant mice are as follows: 1) females develop ovarian tumors and a cachexia-like wasting syndrome, resembling mice lacking inhibin alone. This indicates that the granulosa cells are competent to proliferate despite the lack of GDF9; 2) follicular development progresses to multiple-layer follicle stages before tumorigenesis. This demonstrates that the up-regulation of inhibin in the Gdf9 knockout ovary directly prevents the proliferation of the granulosa cells at the primary follicle stage, an effect that is released in the absence of inhibin ; 3) a morphological theca forms around the preantral follicles with no detectable selective theca markers [i.e. 17-hydroxylase (Cyp17), LH receptor (Lhr), and Kit]. These results indicate that the theca recruitment can occur independently of GDF9, but the differentiation of thecal cells is blocked; and 4) inhibin/activin subunits ßA, ßB, and Kit ligand (Kitl) mRNA are highly up-regulated, suggesting that the increased activins and KITL play functional roles in early folliculogenesis. Thus, GDF9 appears to function indirectly to regulate early granulosa cell proliferation and theca recruitment in vivo.

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