Inhibition of epithelial ductal branching in the prostate by sonic hedgehog is indirectly mediated by stromal cells.
Sonic hedgehog (Shh), a vertebrate homologue of the Drosophila segment-polarity gene hedgehog, has been reported to play an important role during normal development of various tissues. Abnormal activities of Shh signaling pathway have been implicated in tumorigenesis such as basal cell carcinomas and medulloblastomas. Here we show that Shh signaling negatively regulates prostatic epithelial ductal morphogenesis. In organotypic cultures of developing rat prostates, Shh inhibited cell proliferation and promoted differentiation of luminal epithelial cells. The expression pattern of Shh and its receptors suggests a paracrine mechanism of action. The Shh receptors Ptc1 (Patched1) and Ptc2 were found to be expressed in prostatic stromal cells adjacent to the epithelium, where Shh itself was produced. This paracrine model was confirmed by co-culturing the developing prostate in the presence of stromal cells transfected with a vector expressing a constitutively active form of Smoothened, the real effector of the Shh signaling pathway. Furthermore, expression of activin A and TGF-beta1 that were shown previously to inhibit prostatic epithelial branching was up-regulated following Shh treatment in the organotypic cultures. Taken together, these results suggest that Shh negatively regulates prostatic ductal branching indirectly by acting on the surrounding stromal cells, at least partly via up-regulating expression of activin A and TGF-beta1.
Wang
Bu-Er
BE
Department of Molecular Oncology, Genentech, Inc., South San Francisco, California 94080, USA.
Shou
Jianyong
J
Ross
Sarajane
S
Koeppen
Hartmut
H
De Sauvage
Frederic J
FJ
Gao
Wei-Qiang
WQ
D028341:Activins / Q000096:biosynthesis; D000818:Animals; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002454:Cell Differentiation; D002455:Cell Division; D018920:Coculture Techniques; D004847:Epithelial Cells / Q000166:cytology; D004848:Epithelium / Q000378:metabolism; D005786:Gene Expression Regulation; D053823:Hedgehog Proteins; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D028322:Inhibin-beta Subunits / Q000096:biosynthesis; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011467:Prostate / Q000254:growth & development* / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation
D053823:Hedgehog Proteins; D008565:Membrane Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; C000606239:Ptch1 protein, rat; D011956:Receptors, Cell Surface; C508961:Tgfb1 protein, mouse; C508962:Tgfb1 protein, rat; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C422405:activin A; D028341:Activins; D028322:Inhibin-beta Subunits; D001973:Bromodeoxyuridine