title: Generation of Mice with Hepatocyte-Specific Conditional Deletion of Notum.
abstract: BACKGROUND
  Fine tuning of the Wnt/β-catenin signaling pathway is essential for the proper development and function of the liver. Aberrant activation of this pathway is observed in 20%-40% of hepatocellular carcinomas (HCC). Notum encodes a secreted Wnt deacylase that inhibits Wnt activity and thereby restricts the zone of activation of Wnt/β-catenin signaling. An important role of NOTUM has been described in development in drosophila, planaria and zebrafish, but its role in the mammalian liver is unknown. Notum is required for spatial control of the Wnt/β-catenin signaling in several animal models and the Wnt/β-catenin pathway contributes to liver patterning involved in metabolic zonation. Therefore, Notum may be involved in the liver patterning induced by the Wnt/β-catenin signaling during the adult stage.
  
  
  RESULTS
  We generated a conditional Notum knockout mouse mutant to study the effect of the deletion of Notum in the liver. We show that Notum is a direct target of the Wnt/β-catenin signaling in the liver. Liver-specific deletion of Notum did not modify liver zonation, but Notum deletion had a long-term effect on mouse physiology. In particular, male mutant mice developed metabolic disorders.
  
  
  CONCLUSIONS
  We show that Notum is not a key actor of Wnt/β-catenin-dependent liver patterning of adult mice, but has role in liver glucose homeostasis. Male mice deficient in Notum specifically in the liver develop metabolic dysfunctions implicating Notum in the development of Type 2 diabetes.
authors.affiliation: Inserm, U1016, Institut Cochin, 75014 Paris, France.|Cnrs, UMR8104, 75014 Paris, France.|Université Paris Descartes, 75014 Paris, France.|Equipe labellisée LNCC, Paris, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Canal
authors.affiliation: Inserm, U1016, Institut Cochin, 75014 Paris, France.|Cnrs, UMR8104, 75014 Paris, France.|Université Paris Descartes, 75014 Paris, France.|Equipe labellisée LNCC, Paris, France.
authors.forename: Sara
authors.initials: S
authors.lastname: Charawi
authors.affiliation: Inserm, U1016, Institut Cochin, 75014 Paris, France.|Cnrs, UMR8104, 75014 Paris, France.|Université Paris Descartes, 75014 Paris, France.|Equipe labellisée LNCC, Paris, France.
authors.forename: Gisèle
authors.initials: G
authors.lastname: Grimber
authors.affiliation: Inserm, U1016, Institut Cochin, 75014 Paris, France.|Cnrs, UMR8104, 75014 Paris, France.|Université Paris Descartes, 75014 Paris, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Houbron
authors.affiliation: Inserm, U1016, Institut Cochin, 75014 Paris, France.|Cnrs, UMR8104, 75014 Paris, France.|Université Paris Descartes, 75014 Paris, France.|Equipe labellisée LNCC, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Drouet
authors.affiliation: Inserm, U1016, Institut Cochin, 75014 Paris, France.|Cnrs, UMR8104, 75014 Paris, France.|Université Paris Descartes, 75014 Paris, France.|Equipe labellisée LNCC, Paris, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Colnot
authors.affiliation: Inserm, U1016, Institut Cochin, 75014 Paris, France.|Cnrs, UMR8104, 75014 Paris, France.|Université Paris Descartes, 75014 Paris, France.|Equipe labellisée LNCC, Paris, France.|Pathology Unit, Hôpital Cochin, 75014 Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Terris
authors.affiliation: Inserm, U1016, Institut Cochin, 75014 Paris, France.|Cnrs, UMR8104, 75014 Paris, France.|Université Paris Descartes, 75014 Paris, France.|Equipe labellisée LNCC, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Cavard
authors.affiliation: Inserm, U1016, Institut Cochin, 75014 Paris, France.|Cnrs, UMR8104, 75014 Paris, France.|Université Paris Descartes, 75014 Paris, France.|Equipe labellisée LNCC, Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Perret
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics; D004950:Esterases / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D022781:Hepatocytes / Q000201:enzymology*; D008099:Liver / Q000201:enzymology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009928:Organ Specificity; D060449:Wnt Signaling Pathway / Q000235:genetics*
chemical_list: D004950:Esterases