Nuclear progestin receptor (Pgr) knockouts in zebrafish demonstrate role for Pgr in ovulation but not in rapid non-genomic steroid mediated meiosis resumption

Progestins, progesterone derivatives, are the most critical signaling steroid for initiating finaloocyte maturation (FOM) and ovulation, in order to advance fully-grown immature oocytesto become fertilizable eggs in basal vertebrates. It is well-established that progestin inducesFOM at least partly through a membrane receptor and a non-genomic steroid signalingprocess, which precedes progestin triggered ovulation that is mediated through a nuclearprogestin receptor (Pgr) and genomic signaling pathway.To determine whether Pgr plays arole in a non-genomic signaling mechanism during FOM, we knocked out Pgr in zebrafishusing transcription activator-like effector nucleases (TALENs) and studied the oocyte maturation phenotypes of Pgr knockouts (Pgr-KOs). Three TALENs-induced mutant lines withdifferent frame shift mutations were generated. Homozygous Pgr-KO female fish wereall infertile while no fertility effects were evident in homozygous Pgr-KO males. Oocytesdeveloped and underwent FOM normally in vivo in homozygous Pgr-KO female comparedto the wild-type controls, but these mature oocytes were trapped within the follicular cellsand failed to ovulate from the ovaries.These oocytes also underwent normal germinal vesicle breakdown (GVBD) and FOM in vitro, but failed to ovulate even after treatment withhuman chronic gonadotropin (HCG) or progestin (17a,20β-dihydroxyprogesterone or DHP),which typically induce FOM and ovulation in wild-type oocytes. The results indicate thatanovulation and infertility in homozygous Pgr-KO female fish was, at least in part, due to alack of functional Pgr-mediated genomic progestin signaling in the follicular cells adjacentto the oocytes. Our study of Pgr-KO supports previous results that demonstrate a role forPgr in steroid-dependent genomic signaling pathways leading to ovulation, and the firstconvincing evidence that Pgr is not essential for initiating non-genomic progestin signalingand triggering of meiosis resumption

Current Understandings of Core Pathways for the Activation of Mammalian Primordial Follicles

The mammalian ovary has two main functions—producing mature oocytes for fertilization and secreting hormones for maintaining the ovarian endocrine functions. Both functions are vital for female reproduction. Primordial follicles are composed of flattened pre-granulosa cells and a primary oocyte, and activation of primordial follicles is the first step in follicular development and is the key factor in determining the reproductive capacity of females. The recent identification of the phosphatidylinositol 3 kinase (PI3K)/phosphatase and tensin homolog deleted on chromosome 10 (PTEN) signaling pathway as the key controller for follicular activation has made the study of primordial follicle activation a hot research topic in the field of reproduction. This review systematically summarizes the roles of the PI3K/PTEN signaling pathway in primordial follicle activation and discusses how the pathway interacts with various other molecular networks to control follicular activation. Studies on the activation of primordial follicles have led to the development of methods for the in vitro activation of primordial follicles as a treatment for infertility in women with premature ovarian insufficiency or poor ovarian response, and these are also discussed along with some practical applications of our current knowledge of follicular activation