Wnt Signaling in Early Vertebrate Development

Żyłkiewicz, Eliza; Sokol, Sergei Y.; Hoppler, Stefan

doi:10.1002/9781118444122.ch19

Cited by 4 publications

(6 citation statements)

References 157 publications

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“…Early embryos represent ideal experimental models for studying the fundamental molecular mechanisms by which Wnt signalling regulates such context-specific responses, since there are rapid and fundamental changes in the cellular and developmental response to Wnt signalling (reviewed by Zylkiewicz et al, 2014 ). This is particularly prominent in the early Xenopus embryo ( …”

Section: Introductionmentioning

confidence: 99%

Tissue- and stage-specific Wnt target gene expression is controlled subsequent to β‑catenin recruitment

et al. 2016

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Key signalling pathways, such as canonical Wnt/β-catenin signalling, operate repeatedly to regulate tissue- and stage-specific transcriptional responses during development. Although recruitment of nuclear β-catenin to target genomic loci serves as the hallmark of canonical Wnt signalling, mechanisms controlling stage- or tissue-specific transcriptional responses remain elusive. Here, a direct comparison of genome-wide occupancy of β-catenin with a stage-matched Wnt-regulated transcriptome reveals that only a subset of β-catenin-bound genomic loci are transcriptionally regulated by Wnt signalling. We demonstrate that Wnt signalling regulates β-catenin binding to Wnt target genes not only when they are transcriptionally regulated, but also in contexts in which their transcription remains unaffected. The transcriptional response to Wnt signalling depends on additional mechanisms, such as BMP or FGF signalling for the particular genes we investigated, which do not influence β-catenin recruitment. Our findings suggest a more general paradigm for Wnt-regulated transcriptional mechanisms, which is relevant for tissue-specific functions of Wnt/β-catenin signalling in embryonic development but also for stem cell-mediated homeostasis and cancer. Chromatin association of β-catenin, even to functional Wnt-response elements, can no longer be considered a proxy for identifying transcriptionally Wnt-regulated genes. Context-dependent mechanisms are crucial for transcriptional activation of Wnt/β-catenin target genes subsequent to β-catenin recruitment. Our conclusions therefore also imply that Wnt-regulated β-catenin binding in one context can mark Wnt-regulated transcriptional target genes for different contexts.

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Section: Introductionmentioning

confidence: 99%

Tissue- and stage-specific Wnt target gene expression is controlled subsequent to β‑catenin recruitment

et al. 2016

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“…Initially two kinds of direct Wnt/β-catenin target genes were expected in the early embryo (reviewed by Zylkiewicz et al. [2014] , Nakamura and Hoppler [2017] and Esmaeili et al.…”

Section: Discussionmentioning

confidence: 99%

“…Initially two kinds of direct Wnt/b-catenin target genes were expected in the early embryo (reviewed by Zylkiewicz et al [2014], Nakamura and Hoppler [2017] and Esmaeili et al [2020]): direct maternal Wnt/b-catenin target genes, such as sia1 and nodal3 (involved in dorsal specification), and direct zygotic Wnt8a/b-catenin target genes, such as hoxd1 and ventx1 (involved in ventral/lateral specification). Our previous analysis of direct zygotic Wnt8a/b-catenin target genes had revealed at least two contexts (Bmp-regulated and Fgfregulated contexts, .…”

Section: Discussionmentioning

confidence: 99%

“…Wnt signaling, mediated by the intracellular transducer β-catenin (Ctnnb1), plays drastically different roles before and after the maternal-to-zygotic transition (reviewed by Hikasa and Sokol, 2013 ; Zylkiewicz et al., 2014 ). Wnt/β-catenin functions in a regulatory switch mechanism to specify very different cell fates within a narrow window of developmental time.…”

Section: Introductionmentioning

confidence: 99%

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Foxh1/Nodal Defines Context-Specific Direct Maternal Wnt/β-Catenin Target Gene Regulation in Early Development

et al. 2020

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Summary Although Wnt/β-catenin signaling is generally conserved and well understood, the regulatory mechanisms controlling context-specific direct Wnt target gene expression in development and disease are still unclear. The onset of zygotic gene transcription in early embryogenesis represents an ideal, accessible experimental system to investigate context-specific direct Wnt target gene regulation. We combine transcriptomics using RNA-seq with genome-wide β-catenin association using ChIP-seq to identify stage-specific direct Wnt target genes. We propose coherent feedforward regulation involving two distinct classes of direct maternal Wnt target genes, which differ both in expression and persistence of β-catenin association. We discover that genomic β-catenin association overlaps with Foxh1-associated regulatory sequences and demonstrate that direct maternal Wnt target gene expression requires Foxh1 function and Nodal/Tgfβ signaling. Our results support a new paradigm for direct Wnt target gene co-regulation with context-specific mechanisms that will inform future studies of embryonic development and more widely stem cell-mediated homeostasis and human disease.

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“…Using Xenopus as an experimental model organism, two sources of Wnt/βcatenin signalling were identified in early vertebrate embryos: before the onset of zygotic gene expression, also called Zygotic Gene Activation, ZGA, maternal Wnt signalling induces a dorsal axis; and then after the onset of zygotic gene expression, zygotic Wnt8 signalling promotes ventral and lateral mesoderm development; thus suggesting that we might also expect just two corresponding classes of direct Wnt target genes [5,6,7]. Molecular identification of direct Wnt/β-catenin target genes in recent transcriptomics and genomics studies [8,9,10], however, now reveal considerable complexity among Wnt target genes in early development; partly due to co-regulation by other signalling pathways, such as nodal, FGF and BMP signalling [8,10].…”

Section: Introductionmentioning

confidence: 99%

A mathematical modelling portrait of Wnt signalling in early vertebrate embryogenesis

Giuraniuc,

Zain,

Ghafoor

et al. 2022

Preprint

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There are two phases of Wnt signalling in early vertebrate embryogenesis: very early, maternal Wnt signalling promotes dorsal development, and slightly later, zygotic Wnt signalling promotes ventral and lateral mesoderm induction. However, recent molecular biology analysis has revealed more complexity among the direct Wnt target genes, with at least five classes. Here we tested the logic and the dynamics of a new Gene Regulatory Network model suggested by these discoveries using mathematical modelling based on ordinary differential equations (ODEs). Our mathematical modelling of this Gene Regulatory Network reveals that a simplified model, with one "super-gene" for each class is sufficient to a large extent to describe the regulatory behaviour observed experimentally.

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Wnt Signaling in Early Vertebrate Development

Cited by 4 publications

References 157 publications

Tissue- and stage-specific Wnt target gene expression is controlled subsequent to β‑catenin recruitment

Tissue- and stage-specific Wnt target gene expression is controlled subsequent to β‑catenin recruitment

Foxh1/Nodal Defines Context-Specific Direct Maternal Wnt/β-Catenin Target Gene Regulation in Early Development

A mathematical modelling portrait of Wnt signalling in early vertebrate embryogenesis

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