Notch signaling controls liver development by regulating biliary differentiation

Zong, Yiwei; Panikkar, Archana; Xu, Jie; Antoniou, Aline; Raynaud, Peggy; Lemaigre, Frédéric P.; Stanger, Ben Z.

doi:10.1242/dev.029140

Cited by 403 publications

(531 citation statements)

References 54 publications

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“…However hepatic transcription of another Notch target, the transcription factor Hes1 , which has been implicated in the regulation of hepatic lipid metabolism and fatty liver disease (FLD), was unchanged (data not shown) [41]. The levels of mRNAs encoding the Hes1 related genes Hes5 , Hey1 and Hey2 were also unchanged by ICD-E expression, as were Sox9 and Hnf1β (data not shown) [22], [42]. In contrast to the liver, strong induction of Hes5 follows expression of ICD-E in the intestine [20].…”

Section: Resultsmentioning

confidence: 96%

Intestinal Activation of Notch Signaling Induces Rapid Onset Hepatic Steatosis and Insulin Resistance

2011

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Here we investigate the effects of expressing an activated mutant of Notch (ICD-E) in an inducible transgenic mouse model. Hepatic expression of ICD-E in adult animals has no detectable phenotype, but simultaneous induction of ICD-E in both the liver and small intestine results in hepatic steatosis, lipogranuloma formation and mild insulin resistance within 96 hours. This supports work that suggests that fatty liver disease may result from disruption of the gut-liver axis. In the intestine, ICD-E expression is known to produce a transient change in the proportion of goblet cells followed by shedding of the recombinant epithelium. We report additional intestinal transcriptional changes following ICD-E expression, finding significant transcriptional down-regulation of rpL29 (ribosomal protein L29), which is implicated in the regulation of intestinal flora. These results provide further evidence of a gut-liver axis in the development of fatty liver disease and insulin resistance and validate a new model for future studies of hepatic steatosis.

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Section: Resultsmentioning

confidence: 96%

Intestinal Activation of Notch Signaling Induces Rapid Onset Hepatic Steatosis and Insulin Resistance

2011

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“…Because Sox9' a downstream target molecule of Notch signaling19, 23, 24, was frequently co‐expressed in AFP‐positive cells (Fig. 2A), we next examined the relative gene expression levels of canonical Notch ligands in normal and fibrotic liver tissues by real‐time RT‐PCR 25.…”

Section: Resultsmentioning

confidence: 99%

“…Regarding its functions in the liver, it was originally implicated in the regulation of the terminal differentiation of HPCs into biliary epithelial cells23 and/or ductal structure formation in liver development 32, 33, 34. Consistently, mutations in Jagged1 or its major receptor gene Notch2 lead to Alagille syndrome in humans, which is characterized by abnormal formation of the ductal network, causing jaundice 35.…”

Section: Discussionmentioning

confidence: 99%

Identification of a novel alpha‐fetoprotein‐expressing cell population induced by the Jagged1/Notch2 signal in murine fibrotic liver

Nakano

Nakao

Sumiyoshi

et al. 2017

Hepatology Communications

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The liver is well known to possess high regenerative capacity in response to partial resection or tissue injury. However, liver regeneration is often impaired in the case of advanced liver fibrosis/cirrhosis when mature hepatocytes can hardly self‐proliferate. Hepatic progenitor cells have been implicated as a source of hepatocytes in regeneration of the fibrotic liver. Although alpha‐fetoprotein (AFP) is known as a clinical marker of progenitor cell induction in injured/fibrotic adult liver, the origin and features of such AFP‐producing cells are not fully understood. Here, we demonstrate a unique and distinct AFP‐expressing cell population that is induced by the Jagged1/Notch2 signal in murine fibrotic liver. Following repeated carbon tetrachloride injections, a significant number of AFP‐positive cells with high proliferative ability were observed along the fibrous septa depending on the extent of liver fibrosis. These AFP‐positive cells exhibited features of immature hepatocytes that were stained positively for hepatocyte‐lineage markers, such as albumin and hepatocyte nuclear factor 4 alpha, and a stem/progenitor cell marker Sox9. A combination of immunohistological examination of fibrotic liver tissues and coculture experiments with primary hepatocytes and hepatic stellate cells indicated that increased Jagged1 expression in activated hepatic stellate cells stimulated Notch2 signaling and up‐regulated AFP expression in adjacent hepatocytes. The mobilization and proliferation of AFP‐positive cells in fibrotic liver were further enhanced after partial hepatectomy, which was significantly suppressed in Jagged1‐conditional knockout mice. Finally, forced expression of the intracellular domain of Notch2 in normal liver induced a small number of AFP‐expressing hepatocytes in vivo. Conclusion: Insight is provided into a novel pathophysiological role of Jagged1/Notch2 signaling in the induction of AFP‐positive cells in fibrotic liver through the interaction between hepatocytes and activated hepatic stellate cells. (Hepatology Communications 2017;1:215‐229)

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“…3,13 Both families contribute to tumor development, where they can act independently or cooperatively in the regulation of EMT progression. 13 The Notch signaling pathway is known to have a primary role in cell fate determination during organ development, and Notch controls liver development by regulating biliary 14 and hepatoblast 15 differentiation. However, aberrant activation of the Notch pathway has also been shown to be involved in tumorigenesis and the development of EMT in several cancer types.…”

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confidence: 99%

Notch1‐Snail1‐E‐cadherin pathway in metastatic hepatocellular carcinoma

Wang

Zhang

Lui

et al. 2011

Intl Journal of Cancer

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Notch signaling, a critical pathway for tissue development, also contributes to tumorigenesis in many cancers, but its pathological function in liver cancer is not well defined. In our study, Notch1 expression and its clinicopathological parameters were evaluated in 82 human hepatocellular carcinoma (HCC) patients. Plasmid-based siNotch1 shRNA was transiently or stably transfected into metastatic HCC cells and subsequently evaluated for the effects on orthotopic liver tumor metastasis in a mouse model as well as the effects on downstream pathways. Aberrant high expression of Notch1 was significantly associated with metastatic disease parameters in HCC patients, such as tumor-node-metastasis Stages III-IV and tumor venous invasion. Knocking-down Notch1 reduced cell motility in vitro and orthotopic tumor metastasis from the liver to the lung in vivo in a mouse model. In metastatic HCC cells, abnormal expression of Notch1 was associated with increased expression of Snail1 and repressed expression of E-cadherin; the Notch1-Snail1-E-cadherin association can also be found in HCC patient tumors. Inhibition of Notch1 by shRNA abolished Snail1 expression, which further resulted in the reestablishment of repressed E-cadherin in metastatic HCC cells. Thus, abnormal Notch1 expression was strongly associated with HCC metastatic disease, which might be mediated through the Notch1-Snail1-E-cadherin pathway. Knock-down of Notch1 reversed HCC tumor metastasis in a mouse model. Therefore, these data suggest that effective targeting of Notch signaling might also inhibit tumor metastasis.Hepatocellular carcinoma (HCC) is the fifth most common cancer globally and is ranked second amongst all cancer deaths in Hong Kong. HCC is correlated with an increased likelihood of vascular invasion, metastasis and recurrence (even after surgical resection), leading to poor prognosis. 1 Metastasis, both intrahepatic and extrahepatic, is of particular concern and occurs in more than half of HCC cases. 2 The incidence of high grade HCC that metastasize to distant sites is high. 2 However, the detailed mechanisms of metastasis are yet to be revealed.The process that converts adherent epithelial cells into migratory cells to invade the extracellular matrix is called the epithelial-mesenchymal transition (EMT). This process plays fundamental roles in tissue and organ formation during embryonic development and in wound healing and tissue repair during adult life. 3,4 However, the abnormal activation of EMT programs can be disadvantageous to cancer patients. 3 EMT can allow carcinoma cells to acquire mesenchymal cell gene expression profiles and properties, 5 leading to the transformation of the cells from being coherent and displaying apicobasal polarity to become nonpolarized cells that can move through the extracellular media. This transformation enables the spread of tumor cells to distant sites. 6,7 Although EMT is considered to be the first step in the metastatic progression of migratory cancer cells, EMT has not been confirmed to exist in vivo. 3...

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Notch signaling controls liver development by regulating biliary differentiation

Cited by 403 publications

References 54 publications

Intestinal Activation of Notch Signaling Induces Rapid Onset Hepatic Steatosis and Insulin Resistance

Intestinal Activation of Notch Signaling Induces Rapid Onset Hepatic Steatosis and Insulin Resistance

Identification of a novel alpha‐fetoprotein‐expressing cell population induced by the Jagged1/Notch2 signal in murine fibrotic liver

Notch1‐Snail1‐E‐cadherin pathway in metastatic hepatocellular carcinoma

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