Abstract 3262: Role of the Mullerian Ducts in the Development of Genito-Urinary Organs and Coelomic Epithelial Tissues in Female Mice

Abstract Ovarian carcinoma is the most lethal carcinoma arising in female reproductive organ, but the exact site of origin is unclear. It has long been believed that the mesothelial cell layer covers the ovarian surface is the site of origin of these tumors and its role in ovarian tumorigenesis is still being debated. A central issue in this debate is the potential relationship between the coelomic epithelium, from which the ovarian surface mesothelium is derived, and the mullerian ducts, from which most of the female reproductive organs are derived. We created two transgenes, both driven by the Mullerian inhibiting substance type II receptor (MisIIr) promoter (initially obtained from Dr. Denise Connolly, Fox Chase Cancer Center, Philadelphia, PA), respectively expressing beta-galactosidase (LacZ) and Cre recombinase. A minimal promoter sequence, hsp68, was introduced in the beta-galactosidase construct. Expression of MisIIr is known to be present in the mullerian ducts and some of their adult derivatives. We crossed mice carrying the MisIIr-Cre transgene with ROSA 26 (R26R) reporter mice and compared the results of colorimetric assays for beta-galactosidase activity on histological sections from MisIIr-hsp68-LacZ and MisIIr-Cre;R26R transgenic mice of various ages. Detection of enzyme activity in tissues from MisIIr-hsp68-LacZ mice indicated MisIIr promoter activity at the time of the examination whereas expression in tissues derived from MisIIr-Cre;R26R mice also indicated prior activity in ancestral cells, regardless of whether this promoter is active or not at the time of the examination. The upper portion of the vagina, the uterine horns, and the oviducts, which are known to be derived from the mullerian ducts, stained positive for LacZ in MisIIr-Cre;R26R mice as expected. Also positive were ovarian follicles, suggesting an embryological relationship between these structures and the mullerian ducts. No detectable LacZ positivity was present in either the ovarian surface mesothelium or the coelomic epithelium, suggesting a lack of relationship between these tissues and the mullerian ducts. Unexpectedly, a portion of the renal collecting system stained positively in female, but not in male MisIIr-Cre;R26R transgenic mice, raising the possibility of an embryological relationship between the mullerian ducts and some renal tubular cells found in adult kidneys. LacZ positivity was only found in vagina, uterine horns, and oviducts of mice carrying the MisIIr-hsp68-LacZ transgene, suggesting that although ovarian follicular cells and renal tubular cells may be embryologically derived from the mullerian ducts, the MisIIr promoter is either inactive or minimally active in these tissues in adult mice. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3262.