title: Hnf1b controls pancreas morphogenesis and the generation of Ngn3+ endocrine progenitors.
abstract: Heterozygous mutations in the human HNF1B gene are associated with maturity-onset diabetes of the young type 5 (MODY5) and pancreas hypoplasia. In mouse, Hnf1b heterozygous mutants do not exhibit any phenotype, whereas the homozygous deletion in the entire epiblast leads to pancreas agenesis associated with abnormal gut regionalization. Here, we examine the specific role of Hnf1b during pancreas development, using constitutive and inducible conditional inactivation approaches at key developmental stages. Hnf1b early deletion leads to a reduced pool of pancreatic multipotent progenitor cells (MPCs) due to decreased proliferation and increased apoptosis. Lack of Hnf1b either during the first or the secondary transitions is associated with cystic ducts. Ductal cells exhibit aberrant polarity and decreased expression of several cystic disease genes, some of which we identified as novel Hnf1b targets. Notably, we show that Glis3, a transcription factor involved in duct morphogenesis and endocrine cell development, is downstream Hnf1b. In addition, a loss and abnormal differentiation of acinar cells are observed. Strikingly, inactivation of Hnf1b at different time points results in the absence of Ngn3(+) endocrine precursors throughout embryogenesis. We further show that Hnf1b occupies novel Ngn3 putative regulatory sequences in vivo. Thus, Hnf1b plays a crucial role in the regulatory networks that control pancreatic MPC expansion, acinar cell identity, duct morphogenesis and generation of endocrine precursors. Our results uncover an unappreciated requirement of Hnf1b in endocrine cell specification and suggest a mechanistic explanation of diabetes onset in individuals with MODY5.
authors.affiliation: CNRS, UMR7622, Institut de Biologie Paris-Seine (IBPS), Paris F-75005, France Sorbonne Universités, UPMC Université Paris 06, UMR7622-IBPS, Paris F-75005, France INSERM U969, Paris F-75005, France.
authors.forename: Matias G
authors.initials: MG
authors.lastname: De Vas
authors.affiliation: Department of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California-San Diego, La Jolla, CA 92093-0695, USA.
authors.forename: Janel L
authors.initials: JL
authors.lastname: Kopp
authors.affiliation: CNRS, UMR7622, Institut de Biologie Paris-Seine (IBPS), Paris F-75005, France Sorbonne Universités, UPMC Université Paris 06, UMR7622-IBPS, Paris F-75005, France INSERM U969, Paris F-75005, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Heliot
authors.affiliation: Department of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California-San Diego, La Jolla, CA 92093-0695, USA.
authors.forename: Maike
authors.initials: M
authors.lastname: Sander
authors.affiliation: CNRS, UMR7622, Institut de Biologie Paris-Seine (IBPS), Paris F-75005, France Sorbonne Universités, UPMC Université Paris 06, UMR7622-IBPS, Paris F-75005, France INSERM U969, Paris F-75005, France.
authors.forename: Silvia
authors.initials: S
authors.lastname: Cereghini
authors.affiliation: CNRS, UMR7622, Institut de Biologie Paris-Seine (IBPS), Paris F-75005, France Sorbonne Universités, UPMC Université Paris 06, UMR7622-IBPS, Paris F-75005, France INSERM U969, Paris F-75005, France cecile.haumaitre@inserm.fr.
authors.forename: Cécile
authors.initials: C
authors.lastname: Haumaitre
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D003549:Cystic Duct / Q000166:cytology / Q000378:metabolism; D004268:DNA-Binding Proteins; D005260:Female; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D039902:Multipotent Stem Cells / Q000166:cytology / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010179:Pancreas / Q000166:cytology* / Q000378:metabolism*; D011247:Pregnancy; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D051539:Hepatocyte Nuclear Factor 1-beta; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; C478000:Glis3 protein, mouse; C496496:Hnf1b protein, mouse; C407737:Neurog3 protein, mouse
keywords: Cystic ducts; Hnf1b; Human; MODY5; Mouse; Ngn3; Pancreas; Progenitors