Vasorin: a newly identified regulator of ovarian folliculogenesis.

Members of the TGF-ß superfamily take part in the control of folliculogenesis. Vasorin (Vasn) is a newly identified negative regulator of TGF-ß signaling whose possible involvement in ovarian physiology has never been studied. Here, we demonstrate that Vasn is expressed in the ovary by somatic cells of follicles, and that its expression is up-regulated by LH. We established a conditional knockout (cKO) mouse model in which Vasn is deleted specifically in granulosa cells of growing follicles from the secondary stage onwards. Using this model, we show that, upon hormonal stimulation, follicle ovulation size is almost 2-fold higher. This enhanced ovulatory response is associated with overactivation of the TGF-ß signaling pathway and a lower number of atretic antral follicles. Of importance, we demonstrate that the number of primordial follicles is reduced in prepubertal cKO mouse ovaries, which suggests that the production of VASN by growing follicles protects the ovarian reserve. Finally, analysis of systemic KO mice revealed that the ovarian reserve is almost 2.5-fold higher, which implies that Vasn may also play a role in primordial follicle formation. Overall, our findings reveal that Vasn is a new regulator that exerts an effect on several key ovarian functions, including folliculogenesis, maintenance of the ovarian reserve, and ovulation.-Rimon-Dahari, N., Heinemann-Yerushalmi, L., Hadas, R., Kalich-Philosoph, L., Ketter, D., Nevo, N., Galiani, D., Dekel, N. Vasorin: a newly identified regulator of ovarian folliculogenesis.

Ovarian Folliculogenesis.

The ovary, the female gonad, serves as the source for the germ cells as well as the major supplier of steroid sex hormones. During embryonic development, the primordial germ cells (PGCs) are specified, migrate to the site of the future gonad, and proliferate, forming structures of germ cells nests, which will eventually break down to generate the primordial follicles (PMFs). Each PMF contains an oocyte arrested at the first prophase of meiosis, surrounded by a flattened layer of somatic pre-granulosa cells. Most of the PMFs are kept dormant and only a selected population is activated to join the growing pool of follicles in a process regulated by both intra- and extra-oocyte factors. The PMFs will further develop into secondary pre-antral follicles, a stage which depends on bidirectional communication between the oocyte and the surrounding somatic cells. Many of the signaling molecules involved in this dialog belong to the transforming growth factor ß (TGF-ß) superfamily. As the follicle continues to develop, a cavity called antrum is formed. The resulting antral follicles relay on the pituitary gonadotropins, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) for their development. Most of the follicles undergo atretic degeneration and only a subset of the antral follicles, known as the dominant follicles, will reach the preovulatory stage at each reproductive cycle, respond to LH, and subsequently ovulate, releasing a fertilizable oocyte. The remaining somatic cells in the raptured follicle will undergo terminal differentiation and form the corpus luteum, which secretes progesterone necessary to maintain pregnancy.