Increased FOXL2 Expression Alters Uterine Structures and Functions

Abstract

Running Title: FOXL2 overexpression impaires uterus. Summary Sentence: FOXL2 overexpression in the uterus induced epithelial stratification, blunted adenogenesis, increased fibrosis, and disrupted myometrium leading to impaired decidual responses and a similar transcriptome with human endometriosis. Abstract Transcription factor FOXL2 exhibits an increase in mRNA levels in eutopic endometrial biopsy in endometriosis patients. While FOXL2 is known of regulating sex differentiation and reproductive function, the impact of elevated FOXL2 expression on uterine physiology remains unknown. To answer this question, we generated mice with over expression of FOXL2 (FOXL2 OE ) in the female reproductive tract by crossing Foxl2 LsL/+ with the Pgr cre model. FOXL2 OE uterus showed severe morphological abnormality including abnormal epithelial stratification, blunted adenogenesis, increased endometrial fibrosis and disrupted myometrial morphology. In contrast, increasing FOXL2 levels specifically in uterine epithelium by crossing the Foxl2 LsL/+ with the Ltf icre mice resulted in the eFOXL2 OE mice with uterine epithelial stratification but without defects in endometrial fibrosis and adenogenesis, demonstrating a role of the endometrial stroma in the uterine abnormalities of the FOXL2 OE mice. Transcriptomic analysis of 12 weeks old Pgr cre and FOXL2 OE uterus at diestrus stage showed a positive correlation of FOXL2 OE uterine transcriptome with human endometrium of endometriosis patients. Furthermore, we found FOXL2 OE mice were sterile. The infertility was caused in part by a disruption of the hypophyseal ovarian axis resulting in an anovulatory phenotype. The FOXL2 OE mice failed to show decidual responses during artificial decidualization in ovariectomized mice which demonstrates the uterine contribution to the infertility phenotype. These data supported that aberrantly increased FOXL2 expressions in the female reproductive tract can disrupt ovarian and uterine functions, particularly, may be involved in the progressions of endometriosis. Endometriosis is a hormone dependent disease in which uterine endometrial cells grow outside the uterus. The most accepted hypothesis of the origins of endometriosis is that it is t h e peritoneal deposition of endometrial tissue from the retrograde menses that is not cleared by the body [1]. Endometriosis affects about 10 percent of women in the United States [2]. This disease results in pelvic inflammation, pain and infertility and is a significant women's health issue. In women with endometriosis the eutopic endometrium and ectopic extrauterine tissues display altered gene expression signatures [3], including higher expression levels of Forkhead Box L2 (FOXL2) [4, 5]. Studying the role FOXL2 plays in regulating the biology of the reproductive tract will aid in understanding the cause of endometriosis and the development of treatments for this disease. Forkhead Box L2 (FOXL2) is a transcription factor which contains a forkhead domain and a polyalanine tract. In addition to the human en...

Demethylation of Secreted Frizzled-Related Protein2( SFRP2) Promoter Upregulates Wnt/β-Catenin Activity in Endometriosis

“…Many differences were found in gene expression pro les between EMS samples and the normal endometrium tissue samples [4][5][6]. Nowadays, microarray technology has become a mature and stable technology, and during the last decade's bioinformatics analysis has been widely used to identify general genetic of etiology and pathogenesis in many malignant tumors [7][8][9], but there have been few reports of EMS.…”

“…As a common disease, EMS affects about 5%-10% of women of reproductive age, which causes decreases in life quality and is accompanied by symptoms such as pelvic pain and affects more than 10% of reproductive-age women [1,2]. Several classical theories including Mül-Lerianosis, retrograde menstruation, and coelomic metaplasia have been proposed to elucidate the pathogenesis of EMS, but the molecular mechanism is still unknown [3,4].…”