An Indispensable Role of Androgen Receptor in Wnt Responsive Cells during Prostate Development, Maturation, and Regeneration

Androgen signaling is essential for prostate development, morphogenesis, and regeneration. Emerging evidence indicates that Wnt/β-catenin signaling also contributes to prostate development specifically through regulation of cell fate determination. Prostatic Axin2-expressing cells are able to respond to Wnt signals and possess the progenitor properties to regenerate prostatic epithelium. Despite critical roles of both signaling pathways, the biological significance of androgen receptor (AR) in Axin2-expressing Wnt-responsive cells remains largely unexplored. In this study, we investigated this important question using a series of newly generated mouse models. Deletion of Ar in embryonic Axin2-expressing cells impaired early prostate development in both ex vivo and tissue implantation experiments. When Ar expression was deleted in prostatic Axin2-expressing cells at pre-puberty stages, it results in smaller and underdeveloped prostates. A subpopulation of Axin2 expressing cells in prostate epithelium is resistant to castration and, following androgen supplementation, is capable to expand to prostatic luminal cells. Deletion of Ar in these Axin2-expressing cells reduces their regenerative ability. These lines of evidence demonstrate an indispensable role for the Ar in Wnt-responsive cells during the course of prostate development, morphogenesis, and regeneration, which also imply an underlying interaction between the androgen and Wnt signaling pathways in the mouse prostate. This article is protected by copyright. All rights reserved.

Stem cells (Dayton, Ohio). 2018 Feb 16 [Epub ahead of print]

Yongfeng He, Erika Hooker, Eun-Jeong Yu, Huiqing Wu, Gerald R Cunha, Zijie Sun

Department of Cancer Biology, Beckman Research Institute and Cancer Center, City of Hope, Duarte, CA 91010-3000., Department of Pathology, Beckman Research Institute and Cancer Center, City of Hope, Duarte, CA 91010-3000., Department of Urology, School of Medicine, University of California San Francisco, San Francisco, CA 94143.