title: Specification of hepatopancreas progenitors in zebrafish by hnf1ba and wnt2bb.
abstract: Although the liver and ventral pancreas are thought to arise from a common multipotent progenitor pool, it is unclear whether these progenitors of the hepatopancreas system are specified by a common genetic mechanism. Efforts to determine the role of Hnf1b and Wnt signaling in this crucial process have been confounded by a combination of factors, including a narrow time frame for hepatopancreas specification, functional redundancy among Wnt ligands, and pleiotropic defects caused by either severe loss of Wnt signaling or Hnf1b function. Using a novel hypomorphic hnf1ba zebrafish mutant that exhibits pancreas hypoplasia, as observed in HNF1B monogenic diabetes, we show that hnf1ba plays essential roles in regulating β-cell number and pancreas specification, distinct from its function in regulating pancreas size and liver specification, respectively. By combining Hnf1ba partial loss of function with conditional loss of Wnt signaling, we uncover a crucial developmental window when these pathways synergize to specify the entire ventrally derived hepatopancreas progenitor population. Furthermore, our in vivo genetic studies demonstrate that hnf1ba generates a permissive domain for Wnt signaling activity in the foregut endoderm. Collectively, our findings provide a new model for HNF1B function, yield insight into pancreas and β-cell development, and suggest a new mechanism for hepatopancreatic specification.
authors.affiliation: Sanford Children's Health Research Center, Programs in Genetic Disease, Development and Aging, and Stem Cell and Regenerative Biology, Graduate School of Biomedical Sciences, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Lancman
authors.forename: Natasha
authors.initials: N
authors.lastname: Zvenigorodsky
authors.forename: Keith P
authors.initials: KP
authors.lastname: Gates
authors.forename: Danhua
authors.initials: D
authors.lastname: Zhang
authors.forename: Keely
authors.initials: K
authors.lastname: Solomon
authors.forename: Rohan K
authors.initials: RK
authors.lastname: Humphrey
authors.forename: Taiyi
authors.initials: T
authors.lastname: Kuo
authors.forename: Linda
authors.initials: L
authors.lastname: Setiawan
authors.forename: Heather
authors.initials: H
authors.lastname: Verkade
authors.forename: Young-In
authors.initials: YI
authors.lastname: Chi
authors.forename: Ulupi S
authors.initials: US
authors.lastname: Jhala
authors.forename: Christopher V E
authors.initials: CV
authors.lastname: Wright
authors.forename: Didier Y R
authors.initials: DY
authors.lastname: Stainier
authors.forename: P Duc Si
authors.initials: PD
authors.lastname: Dong
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics / Q000378:metabolism*; D043143:Hepatopancreas / Q000166:cytology* / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051153:Wnt Proteins; D029961:Zebrafish Proteins; C496498:hnf1ba protein, zebrafish; C492033:wnt2ba protein, zebrafish; D051539:Hepatocyte Nuclear Factor 1-beta
keywords: Diabetes; Hnf1b; Liver; MODY; Pancreas; Wnt