Gene expression during early follicular development and mechanisms of activation and growth of primordial follicles in mammals

ABSTRACT

Background: For decades, the mechanisms maintaining the dormancy, survival and growth of mammalian primordial follicles as well as their growth up to an early antral stage have been not well understood. In recent years, data obtained from studies on the expression and quantification of mRNA for several growth factors and from studies with genetically modified mouse models have revealed a number of molecules, whose functions are indispensable for (i) the maintenance of follicular quiescence, (ii) primordial follicle survival and (iii) activation, and/or (iv) the growth of primary follicles up to an early antral stage. Review This review focuses on expression of mRNA and protein for growth factors, cytokines and their respective receptors in early follicles, as well as on the intrafollicular signaling cascades that lead to the in-vitro activation of primordial follicles. Furthermore, fundamental information on the levels of mRNA for growth factors at different stages of follicular development and the in-vitro effects of several locally expressed factors on ovarian follicular development will be discussed. During the transition into the primary stage or from the primary into the secondary follicle stage of goats there is a significant increase in the mRNA expression of different factors (BMP-6, BMP-15, KL, EGF, VIP, GDF-9). The detection of these different factors depends on the species. In rat ovaries, GHR is detected in oocytes, granulosa and theca cells. The presence of the mRNA for GHR, but not that for GH has been detected in rat pre-antral follicles. GHR mRNA has only been found in granulosa cells, while positive immunostaining for GHR has been observed in both oocytes and granulosa cells. Also in vitro studies with goat primordial follicles have demonstrated that different factors, estradiol and progesterone promote primordial follicle activation and/or oocyte growth. Recently, several studies have been performed with mouse primordial follicles to understand how intrafollicular cytokines and growth factors may control the fate of primordial follicles in the ovary. In rodents, anti-Mullerian hormone has been shown to inhibit mouse primordial follicle growth and to downregulate c-kit expression in rats, suggesting that, at least in rodents, the kit system plays a key role in initiation of follicular growth. In relation to control of primary and secondary follicles, several in vitro studies have demonstrated that FSH, activin-A, EGF, GH, IGF-I and IGF-II stimulate oocyte growth and follicular development in different species. Conclusion: This review updates the information on expression of mRNA and proteins for growth factors and their role in the regulation of development from primordial to early antral follicles. The growing knowledge of the molecules that control the dormancy, survival, activation and growth of primordial follicles will not only contribute for a better understanding of the physiology of the mammalian ovary, but will also enable researchers to develop more promising methods for promoting growth of oocytes from primordial follicles, the richest follicular resource in the mammalian ovary.