Deletion of Arid1a in Reproductive Tract Mesenchymal Cells Reduces Fertility in Female Mice1

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.

Endometrial epithelial ARID1A is critical for uterine gland function in early pregnancy establishment

“…ARID1A is primarily known for its roles in embryonic development (29) and as a tumor suppressor in many cancers, particularly endometriosis-related cancers of the female reproductive tract (19,22,41). However, recent findings from our group and others have established a role for ARID1A in normal uterine function and in cases of endometriosis without cancer (20, 21,41,42). In this study, we found that ARID1A plays an important role in endometrial gland development and function.…”

Deletion of BAF250a affects oocyte epigenetic modifications and embryonic development

“…A series of studies have determined that BAF250a plays a role in the regulation of heart and brain development (Singh & Archer, 2009; Son & Crabtree, 2014). In addition, BAF250a is required for peri‐implantation development and placenta function (Gao et al, 2008; Kim et al, 2015; Wang, Khatri, Broaddus, Wang, & Hawkins, 2016). Loss of zygotic BAF250a in homozygous mutant mice results in developmental arrest at E6.5 and absence of the mesodermal layer, indicating its critical role in early germ layer formation (Gao et al, 2008).…”

A novel mouse model of testicular granulosa cell tumors

“…In an earlier study, we created a mouse model harboring constitutively active TGFB receptor 1 (TGFBR1) using anti-Mullerian hormone receptor type 2 (Amhr2)-Cre recombinase (Gao et al, 2016). Amhr2-Cre has been widely used to target genes in granulosa and theca cells of the ovary, myometrial and endometrial cells of the uterus (Li et al, 2008(Li et al, , 2011Ren et al, 2009;Wang et al, 2016), and Sertoli cells and Leydig cells of the testis (Boyer et al, 2008). Expression of Amhr2-Cre has been detected as early as 11.5 days post-coitum in the urogenital ridges of both males and females, and the Cre activity is present in the somatic cells of gonads and the mesenchyme of Mullerian ducts (Jamin et al, 2002).…”