Different thresholds of Wnt-Frizzled 7 signaling coordinate proliferation, morphogenesis and fate of endoderm progenitor cells

Perinatal Institute, Division of Developmental Biology, Cincinnati Children's Hospital Medical Center and the College of Medicine, University of Cincinnati, Cincinnati OH 45229 USA.
Developmental Biology (Impact Factor: 3.55). 04/2013; 378(1). DOI: 10.1016/j.ydbio.2013.02.024
Source: PubMed


Wnt signaling has multiple dynamic roles during development of the gastrointestinal and respiratory systems. Differential Wnt signaling is thought to be a critical step in Xenopus endoderm patterning such that during late gastrula and early somite stages of embryogenesis, Wnt activity must be suppressed in the anterior to allow the specification of foregut progenitors. However, the foregut endoderm also expresses the Wnt-receptor Frizzled 7 (Fzd7) as well as several Wnt ligands suggesting that the current model may be too simple. In this study, we show that Fzd7 is required to transduce a low level of Wnt signaling that is essential to maintain foregut progenitors. Foregut-specific Fzd7-depletion from the Xenopus foregut resulted in liver and pancreas agenesis. Fzd7-depleted embryos failed to maintain the foregut progenitor marker hhex and exhibited decreased proliferation; in addition the foregut cells were enlarged with a randomized orientation. We show that in the foregut Fzd7 signals via both the Wnt/β-catenin and Wnt/JNK pathways and that different thresholds of Wnt-Fzd7 activity coordinate progenitor cell fate, proliferation and morphogenesis.

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    • "To test the functional relevance of ATP4a in the context of GI tract ciliation, atp4aSplMO was injected vegetally to target the endoderm (Fig. 5O). Although inhibition of endodermal ATP4a function reduced intestinal foxj1 expression (not shown), it also interfered with normal development of the GI tract (Fig. 5O), a phenotype reminiscent of failure in Wnt-dependent specification of the proximal GI tract [21] "
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    ABSTRACT: During gastrulation and neurulation, foxj1 expression requires ATP4a-dependent Wnt/β-catenin signaling for ciliation of the gastrocoel roof plate [17] and the mucociliary epidermis [19] of Xenopus laevis embryos. These data suggested that ATP4a and Wnt/β-catenin signaling regulate foxj1 throughout Xenopus development. Here we analyzed whether foxj1 expression was also ATP4a-dependent in other ciliated tissues of the developing Xenopus embryo and tadpole. We found that in the floor plate of the neural tube ATP4a-dependent canonical Wnt signaling was required for foxj1 expression, downstream of or in parallel to Hedgehog signaling. In the developing tadpole brain, ATP4-function was a prerequisite for the establishment of cerebrospinal fluid flow. Furthermore, we describe foxj1 expression and the presence of multiciliated cells in the developing tadpole gastrointestinal tract. Our work argues for a general requirement of ATP4-dependent Wnt/β-catenin signaling for foxj1 expression and motile ciliogenesis throughout Xenopus development.
    04/2015; 52. DOI:10.1016/j.dib.2015.04.003
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    • "Recent studies suggest that in some cases, both pathways can be activated in the same cells without resulting in antagonistic effects. For example, Xenopus Wnt5a and Wnt11 jointly activate both branches of the Wnt pathway to promote axis formation (Cha et al., 2008) and gut development (Li et al., 2008; Zhang et al., 2013). The studies described above suggest that, rather than several parallel pathways, the Wnt pathway is a complex molecular network where the cellular context is fundamental to determine which branch is preferentially activated (van Amerongen and Nusse, 2009). "
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    ABSTRACT: Wnts are essential for a multitude of processes during embryonic development and adult homeostasis. The molecular structure of the Wnt pathway is extremely complex, and it keeps growing as new molecular components and novel interactions are uncovered. Recent studies have advanced our understanding on how the diverse molecular outcomes of the Wnt pathway are integrated during organ development, an integration that is also essential, although mechanistically poorly understood, during the formation of the anterior part of the nervous system, the forebrain. Here, I will summarize these findings and discuss their implications for forebrain development. A special emphasis is put on studies performed in the zebrafish since this model system has been instrumental for our current understanding of forebrain patterning. © 2013 Wiley Periodicals, Inc. Develop Neurobiol, 2013.
    Developmental Neurobiology 08/2014; 74(8). DOI:10.1002/dneu.22135 · 3.37 Impact Factor
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    ABSTRACT: Hepatocellular carcinoma (HCC) is one of the most common causes of cancer death worldwide. HCC can be cured by radical therapies if early diagnosis is done while the tumor has remained of small size. Unfortunately, diagnosis is commonly late while the tumor has grown and spread. Thus, palliative approaches are usually applied such as transarterial intrahepatic chemoembolization and sorafenib, an anti-angiogenic agent and MAP kinase inhibitor. This latter is the only targeted therapy that has shown significant, although moderate, efficiency in some individuals with advanced HCC. This highlights the need to develop other targeted therapies, and to this goal, to identify more and more pathways as potential targets. The Wnt pathway is a key component of a physiological process involved in embryonic development and tissue homeostasis. Activation of this pathway occurs when a Wnt ligand binds to a Frizzled (FZD) receptor at the cell membrane. Two different Wnt signaling cascades have been identified, called non-canonical and canonical pathways, the latter involving the β-catenin protein. Deregulation of the Wnt pathway is an early event in hepatocarcinogenesis and has been associated with an aggressive HCC phenotype, since it is implicated both in cell survival, proliferation, migration and invasion. Thus, component proteins identified in this pathway are potential candidates for pharmacological intervention. This review focuses on the characteristics and functions of the molecular targets of the Wnt signaling cascade and how they may be manipulated to achieve anti-tumor effects.
    Journal of Hepatology 07/2013; 9(5). DOI:10.1016/j.jhep.2013.07.001 · 11.34 Impact Factor
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