title: LKB1 and Notch Pathways Interact and Control Biliary Morphogenesis.
abstract: BACKGROUND
  LKB1 is an evolutionary conserved kinase implicated in a wide range of cellular functions including inhibition of cell proliferation, regulation of cell polarity and metabolism. When Lkb1 is inactivated in the liver, glucose homeostasis is perturbed, cellular polarity is affected and cholestasis develops. Cholestasis occurs as a result from deficient bile duct development, yet how LKB1 impacts on biliary morphogenesis is unknown.
  
  
  RESULTS
  We characterized the phenotype of mice in which deletion of the Lkb1 gene has been specifically targeted to the hepatoblasts. Our results confirmed that lack of LKB1 in the liver results in bile duct paucity leading to cholestasis. Immunostaining analysis at a prenatal stage showed that LKB1 is not required for differentiation of hepatoblasts to cholangiocyte precursors but promotes maturation of the primitive ductal structures to mature bile ducts. This phenotype is similar to that obtained upon inactivation of Notch signaling in the liver. We tested the hypothesis of a functional overlap between the LKB1 and Notch pathways by gene expression profiling of livers deficient in Lkb1 or in the Notch mediator RbpJκ and identified a mutual cross-talk between LKB1 and Notch signaling. In vitro experiments confirmed that Notch activity was deficient upon LKB1 loss.
  
  
  CONCLUSIONS
  LKB1 and Notch share a common genetic program in the liver, and regulate bile duct morphogenesis.
authors.affiliation: INSERM, U1016, Institut Cochin, F-75014 Paris, France.|CNRS, UMR8104, F-75014 Paris, France.|Université Paris Descartes, F-75014 Paris, France.|Equipe labellisée LNCC Paris, Paris, France.|APHP, Hôpitaux Universitaires Paris Centre, Hôpital Cochin, Pathology department, F-75014 Paris, France.
authors.forename: Pierre-Alexandre
authors.initials: PA
authors.lastname: Just
authors.affiliation: de Duve Institute and Université catholique de Louvain, B-1200 Brussels, Belgium.
authors.forename: Alexis
authors.initials: A
authors.lastname: Poncy
authors.affiliation: INSERM, U1016, Institut Cochin, F-75014 Paris, France.|CNRS, UMR8104, F-75014 Paris, France.|Université Paris Descartes, F-75014 Paris, France.|Equipe labellisée LNCC Paris, Paris, France.
authors.forename: Sara
authors.initials: S
authors.lastname: Charawi
authors.affiliation: INSERM, U1016, Institut Cochin, F-75014 Paris, France.|CNRS, UMR8104, F-75014 Paris, France.|Université Paris Descartes, F-75014 Paris, France.|Equipe labellisée LNCC Paris, Paris, France.
authors.forename: Rajae
authors.initials: R
authors.lastname: Dahmani
authors.affiliation: INSERM, U1016, Institut Cochin, F-75014 Paris, France.|CNRS, UMR8104, F-75014 Paris, France.|Université Paris Descartes, F-75014 Paris, France.|Equipe labellisée LNCC Paris, Paris, France.
authors.forename: Massiré
authors.initials: M
authors.lastname: Traore
authors.affiliation: INSERM, U1016, Institut Cochin, F-75014 Paris, France.|CNRS, UMR8104, F-75014 Paris, France.|Université Paris Descartes, F-75014 Paris, France.|Equipe labellisée LNCC Paris, Paris, France.
authors.forename: Typhanie
authors.initials: T
authors.lastname: Dumontet
authors.affiliation: INSERM, U1016, Institut Cochin, F-75014 Paris, France.|CNRS, UMR8104, F-75014 Paris, France.|Université Paris Descartes, F-75014 Paris, France.|Equipe labellisée LNCC Paris, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Drouet
authors.affiliation: INSERM, U1016, Institut Cochin, F-75014 Paris, France.|CNRS, UMR8104, F-75014 Paris, France.|Université Paris Descartes, F-75014 Paris, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Dumont
authors.affiliation: INSERM, U1016, Institut Cochin, F-75014 Paris, France.|CNRS, UMR8104, F-75014 Paris, France.|Université Paris Descartes, F-75014 Paris, France.|Equipe labellisée LNCC Paris, Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Gilgenkrantz
authors.affiliation: INSERM, U1016, Institut Cochin, F-75014 Paris, France.|CNRS, UMR8104, F-75014 Paris, France.|Université Paris Descartes, F-75014 Paris, France.|Equipe labellisée LNCC Paris, Paris, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Colnot
authors.affiliation: INSERM, U1016, Institut Cochin, F-75014 Paris, France.|CNRS, UMR8104, F-75014 Paris, France.|Université Paris Descartes, F-75014 Paris, France.|Equipe labellisée LNCC Paris, Paris, France.|APHP, Hôpitaux Universitaires Paris Centre, Hôpital Cochin, Pathology department, F-75014 Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Terris
authors.affiliation: INSERM, UMR991, Université de Rennes 1, F-35033 Rennes, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Coulouarn
authors.affiliation: de Duve Institute and Université catholique de Louvain, B-1200 Brussels, Belgium.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Lemaigre
authors.affiliation: INSERM, U1016, Institut Cochin, F-75014 Paris, France.|CNRS, UMR8104, F-75014 Paris, France.|Université Paris Descartes, F-75014 Paris, France.|Equipe labellisée LNCC Paris, Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Perret
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D000818:Animals; D001650:Bile Duct Neoplasms / Q000378:metabolism / Q000473:pathology; D001652:Bile Ducts / Q000196:embryology* / Q000378:metabolism; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000378:metabolism / Q000473:pathology; D002779:Cholestasis / Q000235:genetics / Q000473:pathology; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000196:embryology; D008822:Mice, Transgenic; D009024:Morphogenesis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*
chemical_list: D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497571:Rbpj protein, mouse; D051880:Receptors, Notch; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; C491654:Stk11 protein, mouse; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases