The phosphoinositide 3-kinase/AKT (protein kinase B) signaling pathway negatively regulates follicle activation via the forkhead box O (FOXO) transcription factor in rodents. FOXO3 knockout mice exhibit global activation of primordial follicles leading to early depletion of ovarian follicles and subsequent infertility. Whether a similar mechanism for follicle activation exists in the primate ovary is unclear. In the current study, protein localization of FOXO1, 3, and 4 as well as their upstream regulator, AKT/p-AKT, was examined in rhesus macaque ovaries of three developmental stages: fetal, prepubertal, and adult. FOXO1 protein is expressed in granulosa cells of fetal, prepubertal, and adult ovaries. FOXO3 is distributed sparsely in the mitotically active germ cells, but its expression decreases following follicle formation in the macaque fetal ovary. In addition, FOXO3 is seldom with interanimal variation in the prepubertal ovary and is absent in the adult ovary. FOXO4 is nondetectable in fetal ovaries, although it is expressed in some theca cells of antral follicles and some stromal cells in prepubertal and adult ovaries. Our results suggest that the regulation and/or function of FOXO3 in the primate primordial follicle may differ than that of the rodent. Nevertheless, AKT/p-AKT is expressed in macaque primordial oocytes, suggesting that similar upstream events but different downstream effects may regulate primordial follicle activation in nonhuman primates compared to rodents. Elucidation of the mechanism responsible for follicle activation in primates will be crucial for understanding primary ovarian insufficiency, improving female fertility, and applying techniques for in vitro maturation of follicles for fertility preservation in cancer survivors.

Summary Sentence

FOXO3 protein localizes in the oocyte of fetal and prepubertal but not adult ovaries while FOXO1 and 4 are expressed in granulosa and theca cells, receptively in the rhesus macaque.