Hepatic Notch2 deficiency leads to bile duct agenesis perinatally and secondary bile duct formation after weaning
(2014) Developmental Biology — Vol. 396, n° 2, p. 201-213 (2014)
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- ("control") mice. Fetal and neonatal Notch2-cKO livers were devoid of cytokeratin19 (CK19)-, Dolichos-biflorus agglutinin (DBA)-, and SOX9-positive ductal structures, demonstrating absence of prenatal cholangiocyte differentiation. Despite extensive cholestatic hepatocyte necrosis and growth retardation, mortality was only ~15%. Unexpectedly, a slow process of secondary cholangiocyte differentiation and bile-duct formation was initiated around weaning that histologically resembled the ductular reaction. Newly formed ducts varied from rare and non-connected, to multiple, disorganized tubular structures that connected to the extrahepatic bile ducts. Jaundice had disappeared in ~30% of Notch2-cKO mice by 6 months. The absence of NOTCH2 protein in postnatally differentiating cholangiocyte nuclei of Notch2-cKO mice showed that these cells had not originated from non-recombined precursor cells. Notch2 and Hnf6 mRNA levels were permanently decreased in Notch2-cKO livers. Perinatally, Foxa1, Foxa2, Hhex, Hnf1β, Cebpα and Sox9 mRNA levels were all significantly lower in Notch2-cKO than control mice, but all except Foxa2 returned to normal or increased levels after weaning, coincident with the observed secondary bile-duct formation. Interestingly, Hhex and Sox9 mRNA levels remained elevated in icteric 6 months old Notch2-cKOs, but decreased to control levels in non-icteric Notch2-cKOs, implying a key role in secondary bile-duct formation. Conclusion: Cholangiocyte differentiation becomes progressively less dependent on NOTCH2 signaling with age, suggesting that ductal-plate formation is dependent on NOTCH2, but subsequent cholangiocyte differentiation is not.
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Falix, F. A., Lamers, W. H., Aronson, D. C., Gaemers, I. C., Lemaigre, F., Hakvoort, T. B. M., de Waart, D. R., Poncy, A., Labruyere, W. T., & Weeda, V. B. (2014). Hepatic Notch2 deficiency leads to bile duct agenesis perinatally and secondary bile duct formation after weaning. Developmental Biology, 396(2), 201-213. https://doi.org/10.1016/j.ydbio.2014.10.002 (Original work published 2014)