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

Proc Natl Acad Sci U S A. 2014 Oct 7;111(40):E4194-203. doi: 10.1073/pnas.1409323111. Epub 2014 Sep 22.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / deficiency*
  • Apoptosis Regulatory Proteins / genetics
  • Autophagy
  • Beclin-1
  • Biosynthetic Pathways / genetics
  • Endosomes / metabolism
  • Endosomes / ultrastructure
  • Female
  • Gene Expression
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Lipid Droplets / metabolism
  • Lipid Droplets / ultrastructure
  • Luteal Cells / metabolism
  • Male
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Microscopy, Electron, Transmission
  • Microscopy, Fluorescence
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Obstetric Labor, Premature / genetics*
  • Ovary / metabolism*
  • Phagosomes / metabolism
  • Phagosomes / ultrastructure
  • Pregnancy
  • Progesterone / biosynthesis*

Substances

  • Apoptosis Regulatory Proteins
  • Beclin-1
  • Becn1 protein, mouse
  • Map1lc3b protein, mouse
  • Microtubule-Associated Proteins
  • Green Fluorescent Proteins
  • Progesterone