Disruption of androgen receptor (AR)-mediated prostate development has been shown to predispose humans and rodents to prostate neoplasia, a leading urologic disease in men. In humans and rodents, the prostate gland forms from the embryonic urogenital sinus (UGS). AR is thought to control the expression of morphogenetic genes in inductive UGS mesenchyme, which in turn promotes proliferation and differentiation of the prostatic epithelium. However, the nature of the AR-regulated morphogenetic genes and the mechanisms whereby AR controls prostate formation are not understood. Our laboratory has identified glial cell line-derived neurotrophic factor (GDNF) and it receptor (GFR?1) as androgen-repressed genes in the UGS and prostate of mice. Consistent with AR-mediated suppression of GDNF signaling, GDNF-GFR?1 signaling via receptor tyrosine kinase RET and non-receptor Src family kinases may serve to inhibit prostate morphogenesis. The goal of this proposed research is to elucidate the function of GDNF signaling in prostate development and determine its regulation by AR signaling. This proposed research is significant because it will lead to a thorough understanding of the central developmental pathways responsible for prostate development, including crosstalk between AR and GDNF signaling pathways. Such understanding will provide crucial clues to the etiology of urogenital disorders and mechanistic insight into key developmental events that reemerge in prostate neoplasia. Identification of signaling nodes that regulate prostate development will inform future drug discovery strategies and therapeutic opportunities for treatment of pathologic prostate cell proliferation and differentiation in the aging male. Preliminary results published from our laboratory using innovative UGS organ culture demonstrate that in the absence of androgen, GDNF increases proliferation of UGS mesenchymal and epithelial cells, which express GFR?1. Consistent with RET localization in the inductive mesenchyme, inhibition of RET selectively blocks GDNF-induced proliferation of mesenchymal cells. We also show that androgen induces proliferation and then differentiation of epithelial cells in the developing prostate, whereas GDNF inhibits the effects of androgen. Further, AR reduces transcription of Gdnf and Gfr?1 while GDNF signaling lessens AR transcription. Therefore, our hypothesis is that GDNF signaling via RET-mediated and RET-independent pathways regulates growth and differentiation of distinct prostate cell types and that reciprocal down-regulation of AR and GDNF signaling functions to orchestrate prostate development. To test this hypothesis, three specific aims are proposed.
Aim 1 will elucidate mechanisms whereby GDNF signaling controls cell proliferation in prostate development.
Aim 2 will deduce mechanisms whereby GDNF signaling regulates cyto-differentiation in prostate formation.
Aim 3 will examine crosstalk between AR and GDNF signaling pathways in prostate development. To achieve these aims, we will use interdisciplinary approaches to assess prostate development and functional crosstalk of AR and GDNF signaling pathways using UGS organ culture and complementary mouse models.
The androgen receptor (AR) mediates prostate development, and disruption of this process predisposes humans and rodents to prostate neoplasia, a leading urologic disease in men. The proposed research will determine the role of glial cell line-derived neurotrophic factor (GDNF) signaling in prostate development and its regulation by AR signaling. Understanding the regulatory crosstalk between AR and GDNF signaling pathways will provide mechanistic insight into key developmental events that reemerge in prostate neoplasia and thus foster the development of therapeutic strategies to combat abnormal cell proliferation and differentiation in the developing prostate gland.
| Park, Hyun-Jung; Bolton, Eric C (2017) RET-mediated glial cell line-derived neurotrophic factor signaling inhibits mouse prostate development. Development 144:2282-2293 |
