Spatially restricted Hedgehog signalling regulates HGF-induced branching of the adult prostate

• Published in: Nature cell biology Vol. 16; no. 12; pp. 1135 - 1145
• Main Authors: Lim, Agnes, Shin, Kunyoo, Zhao, Chen, Kawano, Sally, Beachy, Philip A
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.12.2014
• Subjects: 3' Untranslated Regions - genetics; Animals; Biology; Castration; Cellular signal transduction; Dogs; Down-Regulation; Estrogen Antagonists - pharmacology; Genetic aspects; Hedgehog Proteins - genetics; HEK293 Cells; Hepatocyte Growth Factor - biosynthesis; Hepatocyte Growth Factor - genetics; Humans; Hyperplasia; Kruppel-Like Transcription Factors - biosynthesis; Madin Darby Canine Kidney Cells; Male; Medicine; Mice; Mice, Transgenic; MicroRNA; MicroRNAs - biosynthesis; MicroRNAs - genetics; Microscopy; Morphogenesis; Morpholines - pharmacology; Physiological aspects; Prostate; Prostate - cytology; Prostate - growth & development; Prostate - transplantation; Prostatic Hyperplasia - genetics; Prostatic Hyperplasia - pathology; Purines - pharmacology; Regeneration - genetics; Regeneration - physiology; RNA, Messenger - genetics; Signal Transduction; Stromal Cells - metabolism; Tamoxifen - pharmacology; Testosterone; Testosterone - administration & dosage; Testosterone - biosynthesis; Testosterone - pharmacology; Zinc Finger Protein GLI1; United States; Oregon; United States > US; California
• ISSN: 1465-7392; 1476-4679
• DOI: 10.1038/ncb3057

Branching morphogenesis is thought to be governed by epithelial-stromal interactions, but the mechanisms underlying specification of branch location remain largely unknown. Prompted by the striking absence of Hedgehog (Hh) response at the sites of nascent buds in regenerating tubules of the adult prostate, we investigated the role of Hh signalling in adult prostate branching morphogenesis. We find that pathway activity is localized to stromal cells, and that its attenuation by genetic or pharmacologic manipulation leads to increased branching. Decreased pathway activity correlates with increased stromal production of hepatocyte growth factor (Hgf), and we show that Hgf induces epithelial tubule branching. Regulation of Hgf expression by Hh signalling is indirect, mediated by Hh-induced expression of the microRNAs miR-26a and miR-26b, which in turn downregulate expression of Hgf. Prostate tubule branching thus may be initiated from regions of low Hh pathway activity, with implications for the prostatic hyperplasia commonly observed in late adulthood.