Title

Beclin-1 Deficiency in the Murine Ovary Results in the Reduction of Progesterone Production to Promote Preterm Labor

Abstract

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.

Document Type

Article

Publication Date

10-7-2014

Notes/Citation Information

Published in Proceedings of the National Academy of Sciences of the United States of America, v. 111, no. 40, p. E4194-E4203.

Digital Object Identifier (DOI)

http://dx.doi.org/10.1073/pnas.1409323111

Funding Information

We thank Maggie Murphy for assistance with lipid staining, Wendy Katz for assistance with tissue embedding through support of the University of Kentucky Center of Research in Obesity and Cardiovascular Disease COBRE P20 GM103527-06, and Frontiers in Reproduction for expanding the knowledge of T.R.G. and the science underlying this project. This work was supported by Kentucky Science and Engineering Funds KSEF 2305-RDE-014 and, in part, by a Research Support Grant from the University of Kentucky Office of the Vice President for Research (to E.B.R.), a Gertrude Flora Ribble Fellowship (to T.R.G.), and National Institute of Child Health and Human Development Grant HD061580 (to L.K.C.).