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Ggps1 deficiency in the uterus results in dystocia by disrupting uterine contraction
Yong-Juan Sang1,† , Qiang Wang2,† , Feng Zheng1 , Yue Hua1 , Xin-Ying Wang1 , Jing-Zi Zhang1 , Kang Li1 , Hai-Quan Wang1 , Yue Zhao1 , Min-Sheng Zhu1,* , Hai-Xiang Sun1,* , Chao-Jun Li1,*
1State Key Laboratory of Pharmaceutical Biotechnology, Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University, Nanjing 210093, China
2Department of Neurosurgery, Jingling Hospital, School of Medicine, Nanjing University, Nanjing 210002, China
These authors contributed equally to this work.
*Correspondence to:Min-Sheng Zhu , Hai-Xiang Sun , Chao-Jun Li ,
J Mol Cell Biol, Volume 13, Issue 2, February 2021, 116-127,
Keyword: uterine contraction, protein prenylation, dystocia, statin, RhoA

Dystocia is a serious problem for pregnant women, and it increases the cesarean section rate. Although uterine dysfunction has an unknown etiology, it is responsible for cesarean delivery and clinical dystocia, resulting in neonatal morbidity and mortality; thus, there is an urgent need for novel therapeutic agents. Previous studies indicated that statins, which inhibit the mevalonate (MVA) pathway of cholesterol synthesis, can reduce the incidence of preterm birth, but the safety of statins for pregnant women has not been thoroughly evaluated. Therefore, to unambiguously examine the function of the MVA pathway in pregnancy and delivery, we employed a genetic approach by using myometrial cell-specific deletion of geranylgeranyl pyrophosphate synthase (Ggps1) mice. We found that Ggps1 deficiency in myometrial cells caused impaired uterine contractions, resulting in disrupted embryonic placing and dystocia. Studies of the underlying mechanism suggested that Ggps1 is required for uterine contractions to ensure successful parturition by regulating RhoA prenylation to activate the RhoA/Rock2/p-MLC pathway. Our work indicates that perturbing the MVA pathway might result in problems during delivery for pregnant females, but modifying protein prenylation with supplementary farnesyl pyrophosphate or geranylgeranyl pyrophosphate might be a strategy to avoid side effects.