LKB1 and Notch Pathways Interact and Control Biliary Morphogenesis

Abstract

BackgroundLKB1 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 FindingsWe 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.ConclusionLKB1 and Notch share a common genetic program in the liver, and regulate bile duct morphogenesis.

LKB1 signaling is activated in CTNNB1‐mutated HCC and positively regulates β‐catenin‐dependent CTNNB1‐mutated HCC

“…Here, we showed that LKB1 is overexpressed in CTNNB1 ‐mutated HCC relative to nonmutated HCC and that aberrant activation of β‐catenin signaling induces post‐transcriptional accumulation of LKB1. Using an Lkb1 transcriptomic signature that we recently established using a liver‐specific deletion of Lkb1 in embryonic liver , we confirmed that CTNNB1 ‐mutated HCC express an LKB1 program. In addition, we found that LKB1 is required for specific physiological functions of β‐catenin in the liver and exerts a physiological role as a positive modulator of β‐catenin‐dependent metabolic zonation.…”

“…LKB1KO livemb mutant and control and mice were 3 weeks old. (B) Heat map of the liver β‐catenin target gene signature from the gene expression profile of LKBKO Livemb mice . (C) RT‐qPCR analysis of various positively ( Axin2 , Sp5 , Glul , Lect2 , Cyp2e1 , Nkd1 ) regulated β‐catenin target genes in 14‐day‐old control and LKBKO livemb mutant mice.…”

Crosstalk of LKB1‐regulated and PTEN‐regulated signals in liver morphogenesis and tumor development in mice

“…Recently, it was reported that LKB1 loss leads to dysregulation of Notch and results in disorganized ductal structures (33). Ducts in the LKO mice were reported to be primitive ducts that lack symmetry with no frank disruption of parenchymal hepatocyte organization (17, 33).…”

“…Ducts in the LKO mice were reported to be primitive ducts that lack symmetry with no frank disruption of parenchymal hepatocyte organization (17, 33). We analyzed the Notch signaling profiles in the Pten null livers (GSE70501) using gene set enrichment analysis.…”

“…Loss of LKB1 was reported to result in precocious development of the ductal plate during embryo development (33). This abnormality is thought to be an effect of crosstalk between LKB1 and Notch signaling pathway where downregulation of LKB results in inhibition of Notch regulated gene transcription.…”