{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T18:12:43Z","timestamp":1780337563488,"version":"3.54.1"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2018,4,19]],"date-time":"2018-04-19T00:00:00Z","timestamp":1524096000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"},{"start":{"date-parts":[[2018,4,19]],"date-time":"2018-04-19T00:00:00Z","timestamp":1524096000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2018,6]]},"abstract":"<jats:p>Malformations of the intrahepatic biliary structure cause cholestasis, a liver pathology that corresponds to poor bile flow, which leads to inflammation, fibrosis, and cirrhosis. Although the specification of biliary epithelial cells (BECs) that line the bile ducts is fairly well understood, the molecular mechanisms underlying intrahepatic biliary morphogenesis remain largely unknown. Wnt\/\u03b2\u2010catenin signaling plays multiple roles in liver biology; however, its role in intrahepatic biliary morphogenesis remains unclear. Using pharmacological and genetic tools that allow one to manipulate Wnt\/\u03b2\u2010catenin signaling, we show that in zebrafish both suppression and overactivation of Wnt\/\u03b2\u2010catenin signaling impaired intrahepatic biliary morphogenesis. Hepatocytes, but not BECs, exhibited Wnt\/\u03b2\u2010catenin activity; and the global suppression of Wnt\/\u03b2\u2010catenin signaling reduced Notch activity in BECs. Hepatocyte\u2010specific suppression of Wnt\/\u03b2\u2010catenin signaling also reduced Notch activity in BECs, indicating a cell nonautonomous role for Wnt\/\u03b2\u2010catenin signaling in regulating hepatic Notch activity. Reducing Notch activity to the same level as that observed in Wnt\u2010suppressed livers also impaired biliary morphogenesis. Intriguingly, expression of the Notch ligand genes<jats:italic toggle=\"yes\">jag1b<\/jats:italic>and<jats:italic toggle=\"yes\">jag2b<\/jats:italic>in hepatocytes was reduced in Wnt\u2010suppressed livers and enhanced in Wnt\u2010overactivated livers, revealing their regulation by Wnt\/\u03b2\u2010catenin signaling. Importantly, restoring Notch activity rescued the biliary defects observed in Wnt\u2010suppressed livers.<jats:italic toggle=\"yes\">Conclusion:<\/jats:italic>Wnt\/\u03b2\u2010catenin signaling cell nonautonomously controls Notch activity in BECs by regulating the expression of Notch ligand genes in hepatocytes, thereby regulating biliary morphogenesis. (H<jats:sc>epatology<\/jats:sc>2018;67:2352\u20102366).<\/jats:p>","DOI":"10.1002\/hep.29752","type":"journal-article","created":{"date-parts":[[2017,12,23]],"date-time":"2017-12-23T13:54:18Z","timestamp":1514037258000},"page":"2352-2366","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":29,"title":["Wnt\/\u03b2\u2010catenin signaling controls intrahepatic biliary network formation in zebrafish by regulating notch activity"],"prefix":"10.1097","volume":"67","author":[{"given":"Juhoon","family":"So","sequence":"first","affiliation":[{"name":"Department of Developmental Biology, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine,University of Pittsburgh,Pittsburgh,PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehwish","family":"Khaliq","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology, Pittsburgh Liver Research Center, McGowan Institute for 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L.","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Cell Biology,Stony Brook University,Stony Brook,NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Didier Y.R.","family":"Stainier","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, Programs in Developmental and Stem Cell Biology, Genetics and Human Genetics, Diabetes Center, and Liver Center,University of California, San Francisco,San Francisco,CA"},{"name":"Department of Developmental Genetics,Max Planck Institute for Heart and Lung Research,Bad Nauheim,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donghun","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Developmental Biology, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine,University of 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