title: Spatially restricted Hedgehog signalling regulates HGF-induced branching of the adult prostate.
abstract: 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.
authors.affiliation: 1] Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA [2] Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA [3] Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Agnes
authors.initials: A
authors.lastname: Lim
authors.affiliation: 1] Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA [2] Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305, USA [3] Department of Biochemistry, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Kunyoo
authors.initials: K
authors.lastname: Shin
authors.affiliation: 1] Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA [2] Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305, USA [3] Department of Biochemistry, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhao
authors.affiliation: 1] Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA [2] Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Sally
authors.initials: S
authors.lastname: Kawano
authors.affiliation: 1] Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA [2] Department of Developmental Biology, Stanford University School of Medicine, Stanford, California 94305, USA [3] Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305, USA [4] Department of Biochemistry, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Beachy
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D002369:Castration; D004285:Dogs; D015536:Down-Regulation; D004965:Estrogen Antagonists / Q000494:pharmacology; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000235:genetics*; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D009024:Morphogenesis; D009025:Morpholines / Q000494:pharmacology; D011467:Prostate / Q000166:cytology / Q000254:growth & development* / Q000637:transplantation; D011470:Prostatic Hyperplasia / Q000235:genetics / Q000473:pathology; D011687:Purines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D012038:Regeneration / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology; D013739:Testosterone / Q000008:administration & dosage / Q000096:biosynthesis / Q000494:pharmacology; D000071676:Zinc Finger Protein GLI1
chemical_list: D020413:3' Untranslated Regions; D004965:Estrogen Antagonists; C498520:Gli1 protein, mouse; C553307:HGF protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D035683:MicroRNAs; C543693:Mirn26 microRNA, mouse; D009025:Morpholines; D011687:Purines; D012333:RNA, Messenger; C465570:Shh protein, mouse; D000071676:Zinc Finger Protein GLI1; D013629:Tamoxifen; D013739:Testosterone; D017228:Hepatocyte Growth Factor; C470893:purmorphamine