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.
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