The gene Sonic hedgehog (Shh) encodes a secreted signaling peptide that acts as a potent inducer of growth during fetal development. Secreted Shh peptide binds to a transmembrane receptor Patched (Ptc) and activates the hedgehog (Hh) signal transduction pathway. Hh pathway activation results in specific changes in gene transcription through the actions of 3 related Gli transcription factors. GN1 and Gli2 collaborate to activate transcription of hedgehog (Hh) target genes while Gli3 acts as a transcriptional repressor. Shh-Gli signaling plays a pivotal role in prostate growth regulation. It is necessary for normal ductal morphogenesis, is required for androgen-induced re-growth of the castrate prostate, and has recently been shown to promote prostate cancer growth and metastasis. The major goal of our research is to elucidate the molecular mechanisms by which Hh signaling regulates prostate growth. During the previous cycle of funding, we focused on paracrine signaling. We showed that Shh secreted by the urogenital sinus (UGS) epithelium activates the Hh signal transduction pathway in the UGS mesenchyme. This induces expression of mesenchymal target genes and elicits paracrine signaling mechanisms that regulate epithelial proliferation and differentiation. However, recent evidence suggests that paracrine signaling is not the whole story. Shh also activates the Hh signal transduction pathway in the UGS epithelium and this autocrine signaling appears to play a specific and critical role in regulating the proliferation of epithelial progenitor cells. This proposal addresses the novel hypothesis that Hh-Gli signaling regulates prostate growth by a combination of autocrine and paracrine signaling mechanisms. Specifically, we postulate that autocrine signaling regulates epithelial progenitor cell proliferation while paracrine signaling regulates luminal cell proliferation and differentiation. We will use transgenic Gli1 and Gli2 mutant mice and tissue recombination experiments to quantitatively distinguish the actions of autocrine and paracrine signaling in prostate development. We will use cell based assays to define the mechanisms that regulate autocrine and paracrine signaling and then examine the effect of ectopic autocrine and paracrine signaling on cell proliferation and differentiation in vivo. We expect to show that bifurcation of Hh signaling into autocrine and paracrine actions effectively couples control of progenitor cell proliferation to the regulation of luminal cell proliferation and differentiation. This will introduce a novel paradigm into our efforts to understand normal growth regulation and offer important insights into the role of Hh signaling in prostate cancer where both autocrine and paracrine signaling have been shown to promote tumor growth.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-RUS-B (05))
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Mullins, Christopher V
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University of Wisconsin Madison
Schools of Medicine
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Yu, Min; Bushman, Wade (2013) Differential stage-dependent regulation of prostatic epithelial morphogenesis by Hedgehog signaling. Dev Biol 380:87-98
Shaw, Aubie; Gipp, Jerry; Bushman, Wade (2010) Exploration of Shh and BMP paracrine signaling in a prostate cancer xenograft. Differentiation 79:41-7
Lipinski, Robert J; Bushman, Wade (2010) Identification of Hedgehog signaling inhibitors with relevant human exposure by small molecule screening. Toxicol In Vitro 24:1404-9
Lipinski, Robert J; Song, Chihwa; Sulik, Kathleen K et al. (2010) Cleft lip and palate results from Hedgehog signaling antagonism in the mouse: Phenotypic characterization and clinical implications. Birth Defects Res A Clin Mol Teratol 88:232-40
Zhang, Jingxian; Lipinski, Robert J; Gipp, Jerry J et al. (2009) Hedgehog pathway responsiveness correlates with the presence of primary cilia on prostate stromal cells. BMC Dev Biol 9:50
Yu, Min; Gipp, Jerry; Yoon, Joon Won et al. (2009) Sonic hedgehog-responsive genes in the fetal prostate. J Biol Chem 284:5620-9
Shaw, A; Gipp, J; Bushman, W (2009) The Sonic Hedgehog pathway stimulates prostate tumor growth by paracrine signaling and recapitulates embryonic gene expression in tumor myofibroblasts. Oncogene 28:4480-90
Lipinski, Robert J; Bijlsma, Maarten F; Gipp, Jerry J et al. (2008) Establishment and characterization of immortalized Gli-null mouse embryonic fibroblast cell lines. BMC Cell Biol 9:49
Shaw, Aubie; Attia, Steven; Bushman, Wade (2008) Prostate stromal and urogenital sinus mesenchymal cell lines for investigations of stromal-epithelial interactions. Differentiation 76:599-605
Shi, Xudong; Gipp, Jerry; Bushman, Wade (2007) Anchorage-independent culture maintains prostate stem cells. Dev Biol 312:396-406

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