LKB1 and Notch Pathways Interact and Control Biliary Morphogenesis

PLoS One. 2015 Dec 21;10(12):e0145400. doi: 10.1371/journal.pone.0145400. eCollection 2015.

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.

Methodology/principal findings: 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.

Conclusion: LKB1 and Notch share a common genetic program in the liver, and regulate bile duct morphogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinase Kinases
  • AMP-Activated Protein Kinases
  • Animals
  • Bile Duct Neoplasms / metabolism
  • Bile Duct Neoplasms / pathology
  • Bile Ducts / embryology*
  • Bile Ducts / metabolism
  • Cell Line, Tumor
  • Cholangiocarcinoma / metabolism
  • Cholangiocarcinoma / pathology
  • Cholestasis / genetics
  • Cholestasis / pathology
  • Humans
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein / genetics
  • Immunoglobulin J Recombination Signal Sequence-Binding Protein / metabolism
  • Liver / embryology
  • Mice, Transgenic
  • Morphogenesis
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Receptors, Notch / genetics
  • Receptors, Notch / metabolism*

Substances

  • Immunoglobulin J Recombination Signal Sequence-Binding Protein
  • Rbpj protein, mouse
  • Receptors, Notch
  • Protein Serine-Threonine Kinases
  • STK11 protein, human
  • Stk11 protein, mouse
  • AMP-Activated Protein Kinase Kinases
  • AMP-Activated Protein Kinases

Associated data

  • GEO/GSE75564

Grants and funding

Core fundings came from INSERM, CNRS, grants from Ligue Nationale Contre le Cancer LNCC (France) “Equipe labélisée Ligue Nationale Contre le Cancer” (CP), INCA, ANR and LABEX Who am I? grants (CP). PAJ was a recipient of Poste d’accueil AP-HP-CNRS/CEA. This work was also supported by the Interuniversity Attraction Pole Programme (Belgian Science Policy (BELSPO), grant PVII-47; http://www.belspo.be/) (FL), the D.G. Higher Education and Scientific Research of the French Community of Belgium (grant 10/15-029) (FL), the Alphonse and Jean Forton Fund (grant 2011-R10150-004; http://www.kbs.frb.be/fund.aspxid=293586&langtype=2060) (FL), and the Fonds de la Recherche Scientifique Médicale (grant 3.4536.10F; http://www.fnrs.be/) (FL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.