Molecular Mechanisms Underlying the Activation of Mammalian Primordial Follicles

Abstract

In humans and other mammalian species, the pool of resting primordial follicles serves as the source of developing follicles and fertilizable ova for the entire length of female reproductive life. One question that has intrigued biologists is: what are the mechanisms controlling the activation of dormant primordial follicles. Studies from previous decades have laid a solid, but yet incomplete, foundation. In recent years, molecular mechanisms underlying follicular activation have become more evident, mainly through the use of genetically modified mouse models. As hypothesized in the 1990s, the pool of primordial follicles is now known to be maintained in a dormant state by various forms of inhibitory machinery, which are provided by several inhibitory signals and molecules. Several recently reported mutant mouse models have shown that a synergistic and coordinated suppression of follicular activation provided by multiple inhibitory molecules is necessary to preserve the dormant follicular pool. Loss of function of any of the inhibitory molecules for follicular activation, including PTEN (phosphatase and tensin homolog deleted on chromosome 10), Foxo3a, p27, and Foxl2, leads to premature and irreversible activation of the primordial follicle pool. Such global activation of the primordial follicle pool leads to the exhaustion of the resting follicle reserve, resulting in premature ovarian failure in mice. In this review, we summarize both historical and recent results on mammalian primordial follicular activation and focus on the up-to-date knowledge of molecular networks controlling this important physiological event. We believe that information obtained from mutant mouse models may also reflect the molecular machinery responsible for follicular activation in humans. These advances may provide a better understanding of human ovarian physiology and pathophysiology for future clinical applications.

Activation of dormant ovarian follicles to generate mature eggs

“…Studies using mutant mice indicated that oocyte-specific deletion of the Phosphatase with TENsin homology deleted in chromosome 10 (PTEN) gene promotes the growth of all primordial follicles in neonatal and adult animals (3)(4)(5). The PTEN gene encodes a phosphatase enzyme that negatively regulates the PI3K-Akt signaling pathway.…”

Rictor/mTORC2 Pathway in Oocytes Regulates Folliculogenesis, and Its Inactivation Causes Premature Ovarian Failure

“…To produce mature oocytes for fertilization, primordial follicles are recruited from the reservoir of dormant follicles into the growing follicle pool through a process termed follicular activation, and subsequently undergo a series of development steps. During this entire process, a large number of follicles undergo apoptotic death (atresia) if not selected for further growth (3)(4)(5). Menopause or ovarian failure occurs when the primordial follicle pool is exhausted.…”

Effect of high-fat diet-induced obesity on the Akt/FoxO/Smad signaling pathway and the follicular development of the mouse ovary

“…John et al (12) reported that as the downstream of PI3K/Akt, hyperphosphorylation of FoxO3a induced over-activation of primordial follicules (8,26,28). As previous studies have systematically reported that maintaining optimal activities of PI3K/Akt signaling pathway is essential for normal ovarian function, which not only regulates the balance between survival and activation of primordial follicles, but also is vital for the proliferation and differentiation of GCs (26)(27)(28). These studies suggested that regulation of the optimal expression level of FoxO3a is important spatially and temporally during follicular development.…”

“…In the ovary, primordial follicles are the source of all developing follicles, which have three potential developmental fates: i) To remain quiescent; ii) to be activated into the growing follicle pool; or iii) to undergo death directly from the dormant state (35)(36)(37). Consequently, the balance among these three fates of the primordial follicle determines the length of female reproductive life (27,37,38). Additionally, the bidirectional communication between oocytes and GCs is also important for normal follicular development.…”

“…Previous studies have systematically reported that maintaining optimal activity of Akt serine/threonine kinase 1 (Akt) signaling is essential for normal ovarian function, which regulates the balance between survival and activation of primordial follicles, and also is important for proliferation and differentiation of GCs (26)(27)(28). FoxO3a is also a substrate of Akt, thus, the present study also examined the expression of Akt ovaries.…”