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PNAS 108 (44): 18073-18078

Copyright © 2011 by the National Academy of Sciences.


Heightened uterine mammalian target of rapamycin complex 1 (mTORC1) signaling provokes preterm birth in mice

Yasushi Hirotaa,b,c, Jeeyeon Chaa, Mikihiro Yoshiea, Takiko Daikokua, and Sudhansu K. Deya,1

aDivision of Reproductive Sciences, Perinatal Institute, Cincinnati Children's Research Foundation, Cincinnati, OH 45229; bDepartment of Obstetrics and Gynecology, University of Tokyo, Tokyo 113-8655, Japan; and cPrecursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan

Edited by Bert W. O'Malley, Baylor College of Medicine, Houston, TX, and approved September 23, 2011 (received for review May 22, 2011)

Abstract: Although preterm delivery is a major global health issue, its causes and underlying mechanism remain elusive. Using mutant mice, mimicking aspects of human preterm birth, we show here that uterine decidual senescence early in pregnancy via heightened mammalian target of rapamycin complex 1 (mTORC1) signaling is a significant contributor of preterm birth and fetal death, and that these adverse phenotypes are rescued by a low dose of rapamycin, an inhibitor of mTORC1 signaling. This role of mTORC1 signaling in determining the timing of birth in mice may help us better understand the mechanism of the timing of birth in humans and develop new and improved strategies to combat the global problem of preterm birth.

Key Words: uterus • phospho-S6 • p21 • prostaglandins • parturition

Author contributions: Y.H., J.C., T.D., and S.K.D. designed research; Y.H., J.C., M.Y., T.D., and S.K.D. performed research; Y.H., J.C., M.Y., T.D., and S.K.D. analyzed data; and Y.H., J.C., T.D., and S.K.D. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at

1To whom correspondence should be addressed. E-mail: sk.dey{at}

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