title: Deletion of Arid1a in Reproductive Tract Mesenchymal Cells Reduces Fertility in Female Mice.
abstract: Women with endometriosis can suffer from decreased fecundity or complete infertility via abnormal oocyte function or impaired placental-uterine interactions required for normal pregnancy establishment and maintenance. Although AT-rich interactive domain 1A (SWI-like) (ARID1A) is a putative tumor suppressor in human endometrial cancers and endometriosis-associated ovarian cancers, little is known about its role in normal uterine function. To study the potential function of ARID1A in the female reproductive tract, we generated mice with a conditional knockout of Arid1a using anti-Müllerian hormone receptor 2-Cre Female Arid1a conditional knockout mice exhibited a progressive decrease in number of pups per litter, with a precipitous decline after the second litter. We observed no tumors in virgin mice, although one knockout mouse developed a uterine tumor after pregnancy. Unstimulated virgin female knockout mice showed normal oviductal, ovarian, and uterine histology. Uteri of Arid1a knockout mice showed a normal decidualization response and appropriate responses to estradiol and progesterone stimulation. In vitro studies using primary cultures of human endometrial stromal fibroblasts revealed that small interfering RNA knockdown of ARID1A did not affect decidualization in vitro. Timed pregnancy studies revealed the significant resorption of embryos at Embryonic Day 16.5 in knockout mice in the third pregnancy. In addition to evidence of implantation site hemorrhage, pregnant Arid1a knockout mice showed abnormal placental morphology. These results suggest that Arid1a supports successful pregnancy through its role in placental function.
authors.affiliation: Indiana University, Department of Obstetrics and Gynecology, Indianapolis, Indiana.
authors.forename: Xiyin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Baylor College of Medicine, Department of Obstetrics and Gynecology, Houston, Texas.
authors.forename: Shikha
authors.initials: S
authors.lastname: Khatri
authors.affiliation: University of Texas MD Anderson Cancer Center, Department of Pathology, Houston, Texas.
authors.forename: Russell
authors.initials: R
authors.lastname: Broaddus
authors.affiliation: University of Michigan, Department of Cardiac Surgery, Ann Arbor, Michigan.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Indiana University, Department of Obstetrics and Gynecology, Indianapolis, Indiana shhawkin@iu.edu.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Hawkins
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D010064:Embryo Implantation; D020964:Embryo Loss; D004717:Endometrium / Q000502:physiology; D005260:Female; D005298:Fertility; D005836:Genitalia, Female / Q000378:metabolism*; D006062:Gonadotropins / Q000097:blood; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000209:etiology; D010920:Placenta / Q000378:metabolism; D010929:Placentation; D011247:Pregnancy; D014157:Transcription Factors; D014594:Uterine Neoplasms / Q000209:etiology
chemical_list: C511511:Arid1a protein, mouse; D004268:DNA-Binding Proteins; D006062:Gonadotropins; D009687:Nuclear Proteins; D014157:Transcription Factors
keywords: ARID1A; female reproductive tract; fertility; genetically engineered mouse models; placenta; tumor suppressor; uterus