{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T14:46:00Z","timestamp":1790952360438,"version":"4.1.0"},"reference-count":56,"publisher":"Oxford University Press (OUP)","issue":"24","license":[{"start":{"date-parts":[[2022,7,29]],"date-time":"2022-07-29T00:00:00Z","timestamp":1659052800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01DK113135"],"award-info":[{"award-number":["R01DK113135"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","award":["R01HD093608"],"award-info":[{"award-number":["R01HD093608"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,12,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Polycystic kidney disease (PKD) is a ciliopathy characterized by fluid-filled epithelial cysts in the kidney. Although it is well established that the primary cilium is essential for hedgehog (HH) signaling and HH signaling is abnormally activated in multiple PKD models, the mechanism and function of HH activation in PKD pathogenesis remain incompletely understood. Here we used a transgenic HH reporter mouse line to identify the target tissue of HH signaling in Arl13f\/f;Ksp-Cre mutant kidney, in which the cilia biogenesis gene Arl13b is specifically deleted in epithelial cells of the distal nephron. In addition, we used a co-culture system to dissect cross-talk between epithelial and mesenchymal cells in the absence of expanding cysts. Finally, we treated Arl13bf\/f;Ksp-Cre mice with the GLI inhibitor GANT61 and analyzed its impact on PKD progression in this model. We found that deletion of Arl13b in epithelial cells in the mouse kidney, in vivo, led to non-cell-autonomous activation of the HH pathway in the interstitium. In vitro, when co-cultured with mesenchymal cells, Arl13b\u2212\/\u2212 epithelial cells produced more sonic hedgehog in comparison to cells expressing Arl13b. Reciprocally, HH signaling was activated in mesenchymal cells co-cultured with Arl13b\u2212\/\u2212 epithelial cells. Finally, whole body inhibition of the HH pathway by GANT61 reduced the number of proliferating cells, inhibited cyst progression and fibrosis and preserved kidney function in Arl13bf\/f;Ksp-Cre mice. Our results reveal non-cell-autonomous activation of HH signaling in the interstitium of the Arl13bf\/f;Ksp-Cre kidney and suggest that abnormal activation of the HH pathway contributes to disease progression.<\/jats:p>","DOI":"10.1093\/hmg\/ddac175","type":"journal-article","created":{"date-parts":[[2022,7,29]],"date-time":"2022-07-29T09:59:18Z","timestamp":1659088758000},"page":"4228-4240","source":"Crossref","is-referenced-by-count":15,"title":["Non-cell-autonomous activation of hedgehog signaling contributes to disease progression in a mouse model of renal cystic ciliopathy"],"prefix":"10.1093","volume":"31","author":[{"given":"Chia-Ling","family":"Hsieh","sequence":"first","affiliation":[{"name":"Department of Genetics, Yale University School of Medicine , 333 Cedar St., New Haven, CT 06520, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie Justine","family":"Jerman","sequence":"additional","affiliation":[{"name":"Department of Genetics, Yale University School of Medicine , 333 Cedar St., New Haven, CT 06520, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2307-7719","authenticated-orcid":false,"given":"Zhaoxia","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Genetics, Yale University School of Medicine , 333 Cedar St., New Haven, CT 06520, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,7,29]]},"reference":[{"key":"2022121720472932000_ref1","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1038\/nrg2774","article-title":"The primary cilium: a signalling centre during vertebrate development","volume":"11","author":"Goetz","year":"2010","journal-title":"Nat. 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Nephrol."},{"key":"2022121720472932000_ref5","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.cell.2011.09.014","article-title":"Modeling human disease in humans: the ciliopathies","volume":"147","author":"Novarino","year":"2011","journal-title":"Cell"},{"key":"2022121720472932000_ref6","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1056\/NEJMra1010172","article-title":"Ciliopathies","volume":"364","author":"Hildebrandt","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"2022121720472932000_ref7","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/s41572-018-0047-y","article-title":"Polycystic kidney disease","volume":"4","author":"Bergmann","year":"2018","journal-title":"Nat. Rev. Dis. Primers."},{"key":"2022121720472932000_ref8","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1038\/43913","article-title":"A polycystic kidney-disease gene homologue required for male mating behaviour in C. elegans","volume":"401","author":"Barr","year":"1999","journal-title":"Nature"},{"key":"2022121720472932000_ref9","doi-asserted-by":"crossref","first-page":"5129","DOI":"10.1172\/JCI67273","article-title":"Altered trafficking and stability of polycystins underlie polycystic kidney disease","volume":"124","author":"Cai","year":"2014","journal-title":"J. Clin. Invest."},{"key":"2022121720472932000_ref10","doi-asserted-by":"crossref","first-page":"R378","DOI":"10.1016\/S0960-9822(02)00877-1","article-title":"Polycystin-2 localizes to kidney cilia and the ciliary level is elevated in orpk mice with polycystic kidney disease","volume":"12","author":"Pazour","year":"2002","journal-title":"Curr. 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