title: Let-7b and miR-495 stimulate differentiation and prevent metaplasia of pancreatic acinar cells by repressing HNF6.
abstract: OBJECTIVE
  Diseases of the exocrine pancreas are often associated with perturbed differentiation of acinar cells. MicroRNAs (miRNAs) regulate pancreas development, yet little is known about their contribution to acinar cell differentiation. We aimed to identify miRNAs that promote and control the maintenance of acinar differentiation.
  
  
  METHODS
  We studied mice with pancreas- or acinar-specific inactivation of Dicer (Foxa3-Cre/Dicer(loxP/-) mice), combined (or not) with inactivation of hepatocyte nuclear factor (HNF) 6 (Foxa3-Cre/Dicer(loxP/-)/Hnf6-/- mice). The role of specific miRNAs in acinar differentiation was investigated by transfecting cultured cells with miRNA mimics or inhibitors. Pancreatitis-induced metaplasia was investigated in mice after administration of cerulein.
  
  
  RESULTS
  Inhibition of miRNA synthesis in acini by inactivation of Dicer and pancreatitis-induced metaplasia were associated with repression of acinar differentiation and with induction of HNF6 and hepatic genes. The phenotype of Dicer-deficient acini depends on the induction of HNF6; overexpression of this factor in developing acinar cells is sufficient to repress acinar differentiation and to induce hepatic genes. Let-7b and miR-495 repress HNF6 and are expressed in developing acini. Their expression is inhibited in Dicer-deficient acini, as well as in pancreatitis-induced metaplasia. In addition, inhibiting let-7b and miR-495 in acinar cells results in similar effects to those found in Dicer-deficient acini and metaplastic cells, namely induction of HNF6 and hepatic genes and repression of acinar differentiation.
  
  
  CONCLUSIONS
  Let-7b, miR-495, and their targets constitute a gene network that is required to establish and maintain pancreatic acinar cell differentiation. Additional studies of this network will increase our understanding of pancreatic diseases.
authors.affiliation: Université Catholique de Louvain, de Duve Institute, Brussels, Belgium.
authors.forename: Pierre-Paul
authors.initials: PP
authors.lastname: Prévot
authors.forename: Cécile
authors.initials: C
authors.lastname: Augereau
authors.forename: Alexandru
authors.initials: A
authors.lastname: Simion
authors.forename: Géraldine
authors.initials: G
authors.lastname: Van den Steen
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dauguet
authors.forename: Frédéric P
authors.initials: FP
authors.lastname: Lemaigre
authors.forename: Patrick
authors.initials: P
authors.lastname: Jacquemin
mesh_terms: D061354:Acinar Cells / Q000166:cytology* / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D002108:Ceruletide; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D051559:Hepatocyte Nuclear Factor 6 / Q000378:metabolism*; D007150:Immunohistochemistry; D008679:Metaplasia; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D046790:Pancreas, Exocrine / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D015415:Biomarkers; D051559:Hepatocyte Nuclear Factor 6; C547683:MIRN495 microRNA, mouse; D035683:MicroRNAs; C496606:Onecut1 protein, mouse; C542687:mirnlet7 microRNA, mouse; D002108:Ceruletide
keywords: Amy; Apo; CK19; Cel; Cpa; E; GFP; Gene Regulation; HNF; Mouse Model; P; Pancreatic Development; Proliferation; Prss1; Ptf1a; Rbpj; Try4; amylase; apolipoprotein; carboxyl-ester lipase; carboxypeptidase A; cytokeratin 19; embryonic day; green fluorescent protein; hepatocyte nuclear factor; miRNA; microRNA; pancreas-specific transcription factor subunit 1a; postnatal day; recombining binding protein suppressor of hairless; si; small interfering; trypsin 1; trypsin4