McLin, V. A., Rankin, S. A. & Zorn, A. M. Repression of Wnt/beta-catenin signaling in the anterior endoderm is essential for liver and pancreas development. Development 134, 2207-2217

Cincinnati Children's Research Foundation, Department of Pediatrics, College of Medicine, University of Cincinnati, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
Development (Impact Factor: 6.46). 07/2007; 134(12):2207-17. DOI: 10.1242/dev.001230
Source: PubMed


The liver and pancreas are specified from the foregut endoderm through an interaction with the adjacent mesoderm. However, the earlier molecular mechanisms that establish the foregut precursors are largely unknown. In this study, we have identified a molecular pathway linking gastrula-stage endoderm patterning to organ specification. We show that in gastrula and early-somite stage Xenopus embryos, Wnt/beta-catenin activity must be repressed in the anterior endoderm to maintain foregut identity and to allow liver and pancreas development. By contrast, high beta-catenin activity in the posterior endoderm inhibits foregut fate while promoting intestinal development. Experimentally repressing beta-catenin activity in the posterior endoderm was sufficient to induce ectopic organ buds that express early liver and pancreas markers. beta-catenin acts in part by inhibiting expression of the homeobox gene hhex, which is one of the earliest foregut markers and is essential for liver and pancreas development. Promoter analysis indicates that beta-catenin represses hhex transcription indirectly via the homeodomain repressor Vent2. Later in development, beta-catenin activity has the opposite effect and enhances liver development. These results illustrate that turning Wnt signaling off and on in the correct temporal sequence is essential for organ formation, a finding that might directly impact efforts to differentiate liver and pancreas tissue from stem cells.

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    • "Development of the liver requires coordination between several signalling pathways, such as transforming growth factor í µí»½ (TGF-í µí»½), Wnt, fibroblast growth factor (FGF), Notch, and bone morphogenetic protein (BMP) [8] [9]. Further discussion of these pathways is outside the scope of this review however; they are also active during regeneration in the adult organ [10]. "
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    ABSTRACT: The liver has evolved to become a highly plastic organ with extraordinary regenerative capabilities. What drives liver regeneration is still being debated. Adult liver stem/progenitor cells have been characterized and used to produce functional hepatocytes and biliary cells in vitro. However, in vivo, numerous studies have questioned whether hepatic progenitor cells have a significant role in liver regeneration. Mature hepatocytes have recently been shown to be more plastic than previously believed and give rise to new hepatocytes after acute and chronic injury. In this review, we discuss current knowledge in the field of liver regeneration and the importance of the serotonin pathway as a clinical target for patients with liver dysfunction.
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    • "This result was obtained with Pdx1-Cre early , which induces recombination prior to MPC specification; activation of β-catenin following the secondary transition, with Pdx1-Cre late , results in exocrine pancreas hyperplasia. We suggest that the signaling function of β-catenin is normally inactive prior to MPC specification, and that its hyperactivation at early stages may respecify the organ to an alternative developmental fate (Heller et al., 2002; McLin et al., 2007). "
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    ABSTRACT: Pancreatic exocrine and endocrine lineages arise from multipotent pancreatic progenitor cells (MPCs). Exploiting the mechanisms that govern expansion and differentiation of these cells could enhance efforts to generate β-cells from stem cells. Although our prior work indicates that the canonical Wnt signaling component β-catenin is required qualitatively for exocrine acinar but not endocrine development, precisely how this requirement plays out at the level of MPCs and their lineage-restricted progeny is unknown. In addition, the contribution of β-catenin function to β-cell development remains controversial. To resolve the potential roles of β-catenin in development of MPCs and β-cells, we generated pancreas- and pre-endocrine-specific β-catenin knockout mice. Pancreas-specific loss of β-catenin produced not only a dramatic reduction in acinar cell numbers, but also a significant reduction in β-cell mass. The loss of β-cells is due not to a defect in the differentiation of endocrine precursors, but instead correlates with an early and specific loss of MPCs. In turn, this reflects a novel role for β-catenin in maintaining proximal-distal patterning of the early epithelium, such that distal MPCs resort to a proximal, endocrine-competent "trunk" fate when β-catenin is deleted. Moreover, β-catenin maintains proximal-distal patterning, in part, by inhibiting Notch signaling. Subsequently, β-catenin is required for proliferation of both distal and proximal cells, driving overall organ growth. In distinguishing two distinct roles for β-catenin along the route of β-cell development, we suggest that temporally appropriate positive and negative manipulation of this molecule could enhance expansion and differentiation of stem cell-derived MPCs.
    Developmental Biology 04/2014; 391(1). DOI:10.1016/j.ydbio.2014.03.019 · 3.55 Impact Factor
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    • "In the hindgut, persistent FGF and Wnt signaling are required to maintain Cdx2 expression and define the anterior boundary of the intestine (Gregorieff et al., 2004). At the same time their inhibition is required for proper differentiation of anterior structures such as the stomach, liver and pancreas (Kim et al., 2005; McLin et al., 2007). For instance, (Kim et al., 2005) have shown that Barx1, a homeobox gene whose expression in restricted to stomach mesenchyme during gut formation , is responsible for the repression of Wnt signaling in the stomach through the action of frizzled related proteins (sFRPs), an activity that allows the proper differentiation of the gastric epithelium. "
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    ABSTRACT: The development of the endoderm is a multistage process. From the initial specification of the endodermal domain in the embryo to the final regionalization of the gut, there are multiple stages that require the involvement of complex gene regulatory networks. In one concrete case, the sea urchin embryo, some of these stages and their genetic control are (relatively) well understood. Several studies have underscored the relevance of individual transcription factor activities in the process, but very few have focused the attention on gene interactions within specific gene regulatory networks (GRNs). Sea urchins offer an ideal system to study the different factors involved in the morphogenesis of the gut. Here we review the knowledge gained over the last ten years on the process and its regulation, from the early specification of endodermal lineages to the late events linked to the patterning of functional domains in the gut. A lesson of remarkable importance has been learnt from comparison of the mechanisms involved in gut formation in different bilaterian animals; some of these genetic mechanisms are particularly well conserved. Patterning the gut seems to involve common molecular players and shared interactions, whether we look at mammals or echinoderms. This astounding degree of conservation reveals some key aspects of deep homology that are most probably shared by all bilaterian guts. © 2013 Wiley Periodicals, Inc.
    genesis 03/2014; 52(3). DOI:10.1002/dvg.22738 · 2.02 Impact Factor
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