Anti-Mllerian hormone induces autophagy to preserve the primordial follicle pool in mice

The reserve pool of primordial follicles (PMFs) is finely regulated by molecules implicated in follicular growth or PMF survival. Anti-Mullerian hormone (AMH), produced by granulosa cells of growing follicles, is known for its inhibitory role in the initiation of PMF growth. We observed in a recent in vivo study that injection of AMH into mice seemed to induce an activation of autophagy. Furthermore, injection of AMH into mice activates the transcription factor FOXO3A which is also known for its implication in autophagy regulation. Many studies highlighted the key role of autophagy in the ovary at different stages of folliculogenesis, particularly in PMF survival. Through an in vitro approach with organotypic cultures of prepubertal mouse ovaries, treated or not with AMH, we aimed to understand the link among AMH, autophagy, and FOXO3A transcription factor. Autophagy and FOXO3A phosphorylation were analyzed by western blot. The expression of genes involved in autophagy was quantified by RT-qPCR. In our in vitro model, we confirmed the decrease in FOXO3A phosphorylation and the induction of autophagy in ovaries incubated with AMH. AMH also induces the expression of genes involved in autophagy. Interestingly, most of these genes are known to be FOXO3A target genes. In conclusion, we have identified a new role for AMH, namely the induction of autophagy, probably through FOXO3A activation. Thus, AMH protects the ovarian reserve not only by inhibiting the growth of PMFs but also by enabling their survival through activation of autophagy. AMH decreases the phosphorylation of FOXO3A which is translocated into the nucleus of the PMF oocyte to act as a transcription factor and induce the expression of target genes. FOXO3A inhibits follicular activation which could explain the inhibitory role of AMH in follicular growth. Furthermore, FOXO3A prevents atresia by inducing autophagy genes. The combined actions of FOXO3A lead to PMF quiescence. AMH would protect the reserve pool not only by inhibiting follicular growth but also by inducing autophagy, a role that was unknown until nowadays.image