Activin, a member of the TGF-␤ superfamily, is an important modulator of FSH synthesis and secretion and is involved in reproductive dysfunctions and cancers. It also regulates ovarian follicle development. To understand the mechanisms and pathways by which activin regulates follicle function, we performed a microarray study and identified 240 activin regulated genes in mouse granulosa cells. The gene most strongly inhibited by activin was Cyp26b1, which encodes a P450 cytochrome enzyme that degrades retinoic acid (RA). Cyp26b1 has been shown to play an important role in male germ cell meiosis, but its expression is largely lost in the ovary around embryonic d 12.5. This study demonstrated that Cyp26b1 mRNA was expressed in granulosa cells of follicles at all postnatal developmental stages. A striking inverse spatial and temporal correlation between Cyp26b1 and activin-␤A mRNA expression was observed. Cyp26b1 expression was also elevated in a transgenic mouse model that has decreased activin expression. The Cyp26 inhibitor R115866 stimulated the proliferation of primary cultured mouse granulosa cells, and a similar effect was observed with RA and activin. A pan-RA receptor inhibitor, AGN194310, abolished the stimulatory effect of either RA or activin on granulosa cell proliferation, indicating an involvement of RA receptor-mediated signaling. Overall, this study provides new insights into the mechanisms of activin action in the ovary. We conclude that Cyp26b1 is expressed in the postnatal mouse ovary, regulated by activin, and involved in the control of granulosa cell proliferation. (Endocrinology 152: 303-312, 2011) M ammalian ovarian follicle formation and development involves establishment of the initial follicle pool, follicle growth, proper maturation of eggs, and timely production and release of hormones (1, 2). This process is critical for propagation of the species as well as for development and homeostasis. Regulation of follicle formation and development requires intrinsic and endocrine factors as well as interactions between multiple cell types within the ovary (1-5). Among the many intraovarian factors, substantial evidence indicates that activin and inhibin, members of the TGF-␤ superfamily, play important autocrine/paracrine roles in this process (6 -9). Activin and inhibin were first isolated from gonadal sources as endocrine factors that either stimulate (activin) or suppress (inhibin) the synthesis and secretion of FSH by the pituitary gland (10 -16). Later studies indicated that activin acts predominantly as a local paracrine and autocrine factor (17, 18).

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