This review critically discusses the most recent advances around the role of Notch signaling in liver development homeostasis and disease. targets for agents able to inhibit Notch. However further cell- and context-specific in depth understanding of Notch signaling in liver homeostasis and disease will be essential to translate these concepts into the clinical practice and be able to predict benefits and risks of evolving therapies. or family which execute most biological processes and partially underlie target specificity of different Notch receptor paralogs. However countless other genes can Bosutinib (SKI-606) be also Bosutinib (SKI-606) regulated in parallel of these direct Notch target genes. This may be accomplished by intense cross-talk with other signaling pathways such as the Wnt/��-catenin TGF�� PI3K/AKT Shh HIF-1�� or NF-��B pathway through direct or indirect interactions with Notch signaling components (3) (Fig. 1B). Notch signaling is usually reiteratively used during development of organs and tissues determining the lineage segregation of progenitor cells. Unsurprisingly mutations in Notch genes can result in a variety of hereditary disease syndromes affecting many organs including the Bosutinib (SKI-606) liver (4). However the significance of Notch in determining mammalian cell fates (and functions) during development extends beyond birth and it is Bosutinib (SKI-606) now clear that in adult tissues Notch is also required for tissue homeostasis in self-renewing organs. Notch signaling is frequently reactivated together with other developmental and morphogenic signaling pathways upon organ injury to orchestrate the interplay differentiation and proliferation of distinct cell types and adult progenitors for tissue repair deregulation of which may ultimately result in carcinogenesis. In mammalian livers all Notch ligands and receptors are transcriptionally expressed. However only for few of them there is unequivocal consent about their cell-specific localization. Their functional significance can only be guessed because of the context-specific unpredictable nature of Notch signaling. Mice homozygous for null mutations in most Notch ligand and Bosutinib (SKI-606) receptor genes are of limited use because of mostly embryonic lethality. However availability of conditional cell/tissue-specific Notch loss/gain-of-function animal models has added immensely to our understanding of the diversity of Notch functions in liver development homeostasis injury repair and carcinogenesis (summarized in Fig. 2). There is growing evidence that Notch may also modulate key processes of liver vascular biology liver metabolism and inflammation but the overall effects may greatly differ in distinct liver cell compartments. Consequently modulating Notch signaling by Notch agonistic or antagonistic therapeutic strategies in liver disease may be beneficial in one compartment but may have detrimental side effects in others. Here we summarize recent findings and critically discuss evolving concepts of Notch signaling in the liver. Physique 2 Putative multiple functions of Notch in epithelial lineage control in liver development homeostasis and disease Notch in liver Development A role for the Notch signaling pathway in liver Bosutinib (SKI-606) development was first established in 1997 when genetic studies uncovered mutations in the (and a hypomorphic allele ((mutations have been identified in ALGS patients unfavorable for known mutations (16). Experimental inactivation of both alleles in embryonic hepatoblasts using the mouse strain (or or animals (12 13 17 These Notch-defective mice display periportal irregular ductular structures that appear to arise from some degree of biliary conversion of hepatocytes rather than from the DP (17) and likely represent a rescue Rabbit Polyclonal to RASH. attempt when developmental tubulogenesis of the biliary tree is usually impaired. Ductular reactions (DRs) are variably observed in ALGS patients (18). It is tempting to speculate that the degree of biliary transdifferentiation of hepatocytes is one of the factors responsible for the variable clinical outcome of ALGS. Accordingly in a series of severe ALGS cases requiring liver transplantation ductular structures were absent with an abundance of CK19-/CK7+ hepatocytes likely stuck in the.