Beclin-1 deficiency in the murine ovary results in the reduction of progesterone production to promote preterm labor

Significance The success of mammalian reproduction is contingent upon the production of hormones within the female to not only promote germ cell development, but to establish and maintain pregnancy. We demonstrate that abrogating autophagy, a cellular process to maintain energy stores, can lead to reproductive defects that prevent a successful pregnancy in mice. Females that lack the crucial autophagy gene Beclin1 ( Becn1 ) in the progesterone-producing cells of the ovary demonstrate reduced circulating progesterone and a preterm birth phenotype concurrent with the loss of litters, which is rescued by the administration of exogenous progesterone. Because progesterone is a necessary hormone for mammalian pregnancy, these data suggest that autophagy may play a role in steroidogenesis and, thus, in successful human reproduction. Autophagy is an important cellular process that serves as a companion pathway to the ubiquitin-proteasome system to degrade long-lived proteins and organelles to maintain cell homeostasis. Although initially characterized in yeast, autophagy is being realized as an important regulator of development and disease in mammals. Beclin1 ( Becn1 ) is a putative tumor suppressor gene that has been shown to undergo a loss of heterozygosity in 40–75% of human breast, ovarian, and prostate cancers. Because Becn1 is a key regulator of autophagy, we sought to investigate its role in female reproduction by using a conditional knockout approach in mice. We find that pregnant females lacking Becn1 in the ovarian granulosa cell population have a defect in progesterone production and a subsequent preterm labor phenotype. Luteal cells in this model exhibit defective autophagy and a failure to accumulate lipid droplets needed for steroidogenesis. Collectively, we show that Becn1 provides essential functions in the ovary that are essential for mammalian reproduction.