The Mesenchymal Androgen Receptor and Wolffian Duct Development

The Wolffian ducts (WDs) are paired embryonic structures from which the male urogenital tract will differentiate. The WDs are differentiated from the anterior and intermediate mesoderm in craniocaudal succession. During development the WD exhibits morphological changes as it evolves from a small straight tubule and undergoes proliferation and coiling to eventually generate the epididymis. The role of androgens either directly or via the regulation of other growth factors in the development of the WD and early coiling of the tubule has been well established. In the absence of the androgen receptor the WDs are absent or severely regressed, as is the case where flutamide, an antiandrogen, is administered. During the development of the WDs, the androgen receptor is expressed in both the mesenchyme and the epithelium. While it is well accepted that the mesenchyme plays a crucial role in the development of the epithelium, how this interaction is coordinated with other growth factors and regulators of WD development remains a complex but necessary question to fully understand how these factors regulate the development of the WD and the formation of the epididymis. In the article by Wilbourne et al (1), the authors generated a unique transgenic mouse model to address the significant question regarding the role of the androgen receptor in the WD mesenchyme. Using a constitutive knock-in transgenic mouse model by crossing Osr2-Cre mice with mice containing a floxed androgen receptor, the authors were able to demonstrate that they could specifically knock down the androgen receptor in the WD mesenchyme. In these transgenic mice, the development of the epididymis was impacted by loss of coiling and the formation of cyst-like structures in the anterior region of the WD. Further characterization of this observation using ex vivo explants also supported a role of the mesenchymal androgen receptor in cell proliferation and coiling of the WD. While numerous factors have been shown to regulate cell proliferation, apoptosis, and coiling of the WD, the authors’ data support the notion of the mesenchymal androgen receptor playing a role in orchestrating the regulation of other factors in the development of the WD, even though there did not appear to be an effect on androgen levels. Interestingly, the RNAseq data predict an effect on Sonic Hedgehog (Shh) signaling. Murashima et al (2) reported that the Shh pathways play a role in establishing the positioning of the bilateral WD structures early in development and subsequently in the morphogenesis of the WDs. In a transgenic mouse model in which the primary cilium was reduced and Shh signaling inhibited, it was shown recently that the WD was reduced in size and that the coiling of the epididymis was decreased (3). These mice were also unable to regenerate the epididymal epithelium in adults following efferent duct ligation, suggesting alterations in the stem cell function of epididymal basal cells (4). The WD and resulting epididymis are morphologically and physiologically segment specific. The mesenchymal androgen receptor knockout animal generated by Wilbourne et al (1) shows in both in vivo and ex vivo experiments cauda-specific degeneration of the WD. In the in vivo transgenic model, unilateral degeneration was observed. While the mechanism is not clear it is particularly interesting that these effects may be associated with regulation of bilateral symmetry development of the WDs. It is noteworthy that several of the genes whose expression was altered in the mesenchymal androgen receptor knockout model are associated with epididymal basal cells in the epididymis. Genes such as endothelin 1, angiotensin II, and Cldn1 are all expressed in epididymal basal cells (5). Epididymal basal cell have been proposed as representing a population of adult stem cells in the rat and human epididymis (5). Furthermore, the differentiation of mesenchyme into smooth muscle was also decreased in mesenchymal androgen receptor knockout mice. It has previously been reported that the gap junction protein GJA1 was expressed in smooth muscles of the developing epididymis and that the expression and phosphorylation of GJA1 was androgen dependent (6). Decreased Wnt signaling in the knockout mice is interesting, given that other signaling pathways have also been implicated in the development and stabilization of the WD. During the differentiation of the WD, occludin was localized to the tight junctions of the WD (7). The Cystic Fibrosis Transconductance Regulator (CFTR) regulates the establishment of tight junctions and TJP1 (tight junction protein 1 also known as ZO1). The transcription factor ZO-1–associated nucleic acid binding (ZONAB) protein signaling pathway is also involved in the differentiation of the WD in the mouse. In CFTR-null rats, the WD appears normal throughout embryonic development, and the efferent ducts and epididymis undergo atresia between birth and postnatal day 4. Interestingly, the smooth muscle that surrounds epididymal epithelia was reduced as was epididymal coiling. RNAseq analysis suggest that Wnt signaling was altered in the epididymis of these animals. Wnt signaling has also been shown to play an important role in WD development and epididymal coiling. Genetic ablation of Wnt signaling results in decreased cell proliferation, coiling, and increased apoptosis. Lineage tracing of early postnatal epididymal development suggested that columnar cells differentiate into basal, principal, clear, narrow, and apical cells (8). Their results indicated that cell proliferation during this phase of epididymal development was regulated by the Wnt/Beta-catenin (Ctnnb1) signaling pathway but that cell differentiation was not regulated by Ctnnb1 signaling. Clearly the development of transgenic mice for understanding the complex regulatory interactions implicated in the regulation of the WD development and epididymis is critical for our understanding of male development and fertility. The development of a mesenchymal androgen receptor knockout mouse model by Wilbourne et al (1) provides a novel tool which will contribute to a much-needed understanding of WD development. Support from a Canada Research Chair in Reproductive Toxicology is gratefully acknowledged. The author declares no conflict of interest. Cystic Fibrosis Transconductance Regulator Wnt/Beta-catenin Sonic Hedgehog Wolffian duct

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