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Endocrinology

Title:		Deletion of RhoA in Progesterone Receptor-Expressing Cells Leads to Luteal Insufficiency and Infertility in Female Mice
Author(s):		El Zowalaty AE; Li R; Zheng Y; Lydon JP; DeMayo FJ; Ye X;
Address:		"Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, Georgia 30602. Interdisciplinary Toxicology Program, University of Georgia, Athens, Georgia 30602. Division of Experimental Hematology and Cancer Biology, Children's Hospital Research Foundation, Cincinnati, Ohio 45229. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030. Reproductive and Developmental Biology Laboratory/Pregnancy and Female Reproduction Group, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709"
Journal Title:		Endocrinology
Year:		2017
Volume:		158
Issue:		7
Page Number:		2168 - 2178
DOI:		10.1210/en.2016-1796
ISSN/ISBN:		1945-7170 (Electronic) 0013-7227 (Print) 0013-7227 (Linking)
Abstract:		"Ras homolog gene family, member A (RhoA) is widely expressed throughout the female reproductive system. To assess its role in progesterone receptor-expressing cells, we generated RhoA conditional knockout mice RhoAd/d (RhoAf/f-Pgr-Cre+/-). RhoAd/d female mice had comparable mating activity, serum luteinizing hormone, prolactin, and estradiol levels and ovulation with control but were infertile with progesterone insufficiency, indicating impaired steroidogenesis in RhoAd/d corpus luteum (CL). RhoA was highly expressed in wild-type luteal cells and conditionally deleted in RhoAd/d CL. Gestation day 3.5 (D3.5) RhoAd/d ovaries had reduced numbers of CL, less defined corpus luteal cord formation, and disorganized CL collagen IV staining. RhoAd/d CL had lipid droplet and free cholesterol accumulation, indicating the availability of cholesterol for steroidogenesis, but disorganized beta-actin and vimentin staining, indicating disrupted cytoskeleton integrity. Cytoskeleton is important for cytoplasmic cholesterol movement to mitochondria and for regulating mitochondria. Dramatically reduced expression of mitochondrial markers heat shock protein 60 (HSP60), voltage-dependent anion channel, and StAR was detected in RhoAd/d CL. StAR carries out the rate-limiting step of steroidogenesis. StAR messenger RNA expression was reduced in RU486-treated D3.5 wild-type CL and tended to be induced in progesterone-treated D3.5 RhoAd/d CL, with parallel changes of HSP60 expression. These data demonstrated the in vivo function of RhoA in CL luteal cell cytoskeleton integrity, cholesterol transport, StAR expression, and progesterone synthesis, and a positive feedback on StAR expression in CL by progesterone signaling. These findings provide insights into mechanisms of progesterone insufficiency"
Keywords:		"Animals Corpus Luteum/metabolism Corpus Luteum Maintenance/*genetics Female Gene Deletion Infertility, Female/*genetics Luteal Cells/*metabolism Male Mice Mice, Knockout Ovary/metabolism Pregnancy Progesterone/deficiency/metabolism Receptors, Progesterone;"
Notes:		"MedlineEl Zowalaty, Ahmed E Li, Rong Zheng, Yi Lydon, John P DeMayo, Francesco J Ye, Xiaoqin eng P50 HD028934/HD/NICHD NIH HHS/ R01 HD065939/HD/NICHD NIH HHS/ R15 HD066301/HD/NICHD NIH HHS/ Research Support, N.I.H., Extramural 2017/05/13 Endocrinology. 2017 Jul 1; 158(7):2168-2178. doi: 10.1210/en.2016-1796"