RF34 | PMON254 Why Does Androgens Fail to Promote the Survival of the Wolffian Duct in the Absence of Wnt9b?

Abstract

Abstract The male reproductive tract development has been predominantly dependent upon androgen action, which is mainly mediated by the androgen receptor (AR). Under the influence of androgen actions, the primitive male reproductive tract, also known as the Wolffian duct, is first stabilized then differentiates into the epididymis, vas deference and seminal vesicle. Impairment of androgen signaling during fetal programming causes a spectrum of male reproductive disorders that manifest in adulthood. Despite the dominant roles of androgen action in the male reproductive tract development, it has been noticed that androgen's capability in promoting Wolffian duct survival and development is completely lost in the absence of Wnt9b. Wnt9b belongs to the WNT family of secreted proteins. It is specifically expressed in the Wolffian duct epithelium to regulate the surrounding mesenchyme. This project aims to investigate why the androgen action fails to maintain the male reproductive tract in the absence of Wnt9b. We first examined the expression pattern of Wnt9b during the window of sexual differentiation, which was not investigated in the previous publication. We found that during sexual differentiation, Wnt9b is still specifically expressed in the Wolffian duct epithelium in both XX and XY embryos. Androgen action exists in XY but not in the XX embryos during sexual differentiation. These observations indicate that Wnt9b does not lie downstream of the androgen signaling. We are in process of collecting Wnt9b+/+ and Wnt9b-/- male embryos to examine whether expression of AR and AR downstream genes is altered in the absence of Wnt9b. In addition, WNT9B can activate two intracellular pathways under the context of target cells: β-catenin dependent and independent pathways. Since Wolffian duct mesenchyme is the major target of epithelium-derived WNT9B, we next determined which pathways WNT9B acts through in the mesenchyme by specific deletion of β-catenin in the Wolffian duct mesenchyme. Interestingly, the loss of β-catenin in the mesenchyme led to the partial degeneration of Wolffian ducts at the caudal region and cystic formations at the cranial region, the similar phenotypes observed in mesenchymal AR knockout male embryos. Taken together, our study demonstrates that the local WNT9B/β-catenin pathway provides the permissive signaling for androgen actions in Wolffian duct development. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 1:12 p.m. - 1:17 p.m.