Uterine Cysts in Female Mice Deficient for Caveolin-1 and Insulin-Like 3 Receptor RXFP2

Abstract

Gene mutations of insulin-like 3 (INSL3) peptide or its G protein-coupled receptor RXFP2 (relaxin family peptide receptor 2) lead to cryptorchidism. The role of INSL3 in adult females is less known, although INSL3 expression has been described in female reproductive organs. Caveolin-1 (CAV1), the main component of caveoli cell membrane invaginations, has been shown to play an important role in epithelial organization and stromal-epithelial interactions. We created a null allele of Cav1 mice by deleting its second exon through embryonic stem cell targeting. Immunohistochemical analysis demonstrated that CAV1 expression was primarily localized to endothelial blood vessel cells and the myometrium uterus, whereas the strongest expression of Rxfp2 was detected in the endometrial epithelium. By 12 months of age approximately 18% of Cav1-/- females developed single or multiple dilated endometrial cysts lined by a flattened, simple low epithelium. A deficiency for Rxfp2 on Cav1-deficient background led to more than a 2-fold increase in the incidence of uterine cysts (54-58%). Appearance of cysts led to a severe disorganization of uterine morphology. We have found that the cysts had an increased expression of β-catenin and estrogen receptor β in endometrial stromal and epithelial cells and increased epithelial proliferation. An analysis of simple dilated cysts in human patients for CAV1 expression did not show appreciable differences with control regardless of menstrual phase, suggesting an involvement of additional factors in human disease. The results of this study suggest a novel synergistic role of INSL3/RXFP2 and CAV1 in structural maintenance of the uterus.