Wnt Signaling from Development to Disease: Insights from Model Systems

Cadigan, Ken M.; Peifer, Mark

doi:10.1101/cshperspect.a002881

Cited by 274 publications

(270 citation statements)

References 213 publications

(250 reference statements)

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“…As the vast majority of Wnt signaling during C. elegans development involves b-catenin-dependent signaling, in this review we will consider only the Wnt/b-catenin signaling pathway elucidated from vertebrate and Drosophila studies ( Fig. 1; pathway function reviewed in Cadigan and Peifer 2009;MacDonald et al 2009). …”

Section: The Conserved Metazoan Wnt/ B-catenin Signaling Pathwaymentioning

confidence: 99%

“…This evolutionary conservation suggests that cellular signaling mechanisms functioning in response to Wnts were part of the "developmental toolkit" in place at least 500 million years ago in the common ancestor to modern metazoans (Guder et al 2006). Signaling regulated by Wnt ligand binding plays an important and often essential role in an astounding number of processes during invertebrate and vertebrate development, as well as functioning in the maintenance of adult stem cell populations in vertebrates and Drosophila (reviewed in Clevers 2006;Cadigan and Peifer 2009;MacDonald et al 2009). In the nematode Caenorhabditis elegans, Wnt signaling is necessary for many events during both embryonic and larval development, and regulates many processes including cell migration, cell polarity, fate specification, axon guidance, synaptogenesis, and stem cell-like renewal (see Eisenmann 2005;Mizumoto and Sawa 2007b;Van Hoffelen and Herman 2008).…”

mentioning

confidence: 99%

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-Catenin-Dependent Wnt Signaling in C. elegans: Teaching an Old Dog a New Trick

Jackson

Eisenmann

2012

Cold Spring Harbor Perspectives in Biology

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Section: The Conserved Metazoan Wnt/ B-catenin Signaling Pathwaymentioning

confidence: 99%

mentioning

confidence: 99%

-Catenin-Dependent Wnt Signaling in C. elegans: Teaching an Old Dog a New Trick

Jackson

Eisenmann

2012

Cold Spring Harbor Perspectives in Biology

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“…However, it is not clear whether Wnt activity is simply not relevant to anterior development, or must be carefully regulated. The molecular functions of canonical Wnt pathway components are highly conserved between Drosophila and vertebrates (9). Assuming they are similarly conserved in other insects, we examined expression and function of axin in Tribolium embryos.…”

mentioning

confidence: 99%

Asymmetrically expressed axin required for anterior development in Tribolium

Posnien

Bolognesi

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Canonical Wnt signaling has been implicated in an AP axis polarizing mechanism in most animals, despite limited evidence from arthropods. In the long-germ insect, Drosophila, Wnt signaling is not required for global AP patterning, but in short-germ insects including Tribolium castaneum, loss of Wnt signaling affects development of segments in the growth zone but not those defined in the blastoderm. To determine the effects of ectopic Wnt signaling, we analyzed the expression and function of axin, which encodes a highly conserved negative regulator of the pathway. We found Tc-axin transcripts maternally localized to the anterior pole in freshly laid eggs. Expression spread toward the posterior pole during the early cleavage stages, becoming ubiquitous by the time the germ rudiment formed. Tc-axin RNAi produced progeny phenotypes that ranged from mildly affected embryos with cuticles displaying a graded loss of anterior structures, to defective embryos that condensed at the posterior pole in the absence of serosa. Altered expression domains of several blastodermal markers indicated anterior expansion of posterior fates. Analysis of other canonical Wnt pathway components and the expansion of Tc-caudal expression, a Wnt target, suggest that the effects of Tc-axin depletion are mediated through this pathway and that Wnt signaling must be inhibited for proper anterior development in Tribolium. These studies provide unique evidence that canonical Wnt signaling must be carefully regulated along the AP axis in an arthropod, and support an ancestral role for Wnt activity in defining AP polarity and patterning in metazoan development.A-P axis patterning | short-germ segmentation | anterior patterning | maternal determination

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“…The canonical Wnt signalling pathway has been studied extensively, since it has been experimentally proven to have a major impact on cell proliferation, migration and fate decisions as apoptosis and differentiation [1][2][3][4]. Dysfunctions within the pathway can lead to serious consequences, such as osteoporosis, cancer, and neurodegenerative diseases (reviewed in [5][6][7][8][9]).…”

Section: The Wnt Signalling Pathwaymentioning

confidence: 99%

Nucleo-cytoplasmic shuttling of APC can maximize β‐catenin/TCF concentration

Schmitz¹,

Rateitschak²

2011

Journal of Theoretical Biology

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Abstractβ-catenin is the key player of the canonical Wnt pathway. Its activity is mainly regulated via protein degradation.In the nucleus, its interaction with TCF initiates target gene expression. Although the functional relevance is unclear, it has been shown that β-catenin antagonists are also capable of nucleo-cytoplasmic shuttling. The focus of our systems biology analysis lies on the β-catenin subcellular distribution regulated by the antagonist and scaffolding protein APC. We address the following questions: Can the concentration of the transcription factor complex [β-catenin/TCF], which is considered as the output of the pathway, be maximized by APC nucleo-cytoplasmic shuttling and how is retention of β-catenin by APC influencing this output?We established a mathematical model based on experimental findings to examine the influence of nucleocytoplasmic shuttling of APC and retention of β-catenin by APC on the output of the pathway. The model is based on ordinary differential equations and includes protein shuttling between the two compartments nucleus and cytoplasm as well as protein complex formation in each compartment. We discuss how the steady state concentration of [β-catenin/TCF] is influenced by APC shuttling and retention. The analysis of the model shows that the breakdown of β-catenin cytoplasmic retention induced by APC shuttling can enhance nuclear accumulation of β-catenin and hence maximize the output of the pathway.Using mathematical modelling, we demonstrate that in certain parameter ranges, the steady state concentration of [β-catenin/TCF] benefits from APC shuttling. The inhibitory effect of APC is alleviated due to shuttling of APC. Surprisingly, our study therefore indicates that the nucleo-cytoplasmic shuttling of APC can have a beneficial effect on the output of the pathway in steady state, although APC is in general a β-catenin antagonizing protein.Furthermore, we show that saturated protein translocation can under certain conditions be modelled by pure diffusion. A difference in the shuttling rate constants of sufficient orders of magnitude leads to an accumulation in either compartment, which corresponds to saturation in translocation.

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Wnt Signaling from Development to Disease: Insights from Model Systems

Cited by 274 publications

References 213 publications

-Catenin-Dependent Wnt Signaling in C. elegans: Teaching an Old Dog a New Trick

-Catenin-Dependent Wnt Signaling in C. elegans: Teaching an Old Dog a New Trick

Asymmetrically expressed axin required for anterior development in Tribolium

Nucleo-cytoplasmic shuttling of APC can maximize β‐catenin/TCF concentration

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