The Wnt/beta-catenin pathway regulates cardiac valve formation

A.F. Hurlstone; A.P. Haramis; E. Wienholds; H.L. Begthel; J. Korving; F. van Eeden; E. Cuppen; D. Zivkovic; R. Plasterk; J.C. Clevers

doi:10.1038/nature02028

The Wnt/beta-catenin pathway regulates cardiac valve formation

A.F. Hurlstone, A.P. Haramis, E. Wienholds, H.L. Begthel, J. Korving, F. van Eeden, E. Cuppen, D. Zivkovic, R. Plasterk, J.C. Clevers

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

357 Citations (Scopus)

Abstract

Truncation of the tumour suppressor adenomatous polyposis coli (Apc) constitutively activates the Wnt/beta-catenin signalling pathway. Apc has a role in development: for example, embryos of mice with truncated Apc do not complete gastrulation. To understand this role more fully, we examined the effect of truncated Apc on zebrafish development. Here we show that, in contrast to mice, zebrafish do complete gastrulation. However, mutant hearts fail to loop and form excessive endocardial cushions. Conversely, overexpression of Apc or Dickkopf 1 (Dkk1), a secreted Wnt inhibitor, blocks cushion formation. In wild-type hearts, nuclear beta-catenin, the hallmark of activated canonical Wnt signalling, accumulates only in valve-forming cells, where it can activate a Tcf reporter. In mutant hearts, all cells display nuclear beta-catenin and Tcf reporter activity, while valve markers are markedly upregulated. Concomitantly, proliferation and epithelial-mesenchymal transition, normally restricted to endocardial cushions, occur throughout the endocardium. Our findings identify a novel role for Wnt/beta-catenin signalling in determining endocardial cell fate.

Original language	English
Pages (from-to)	633-637
Journal	Nature
Volume	425
Issue number	6958
DOIs	https://doi.org/10.1038/nature02028
Publication status	Published - 2003

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@article{f5611781600241c3bdbbb21b697ddd19,

title = "The Wnt/beta-catenin pathway regulates cardiac valve formation",

abstract = "Truncation of the tumour suppressor adenomatous polyposis coli (Apc) constitutively activates the Wnt/beta-catenin signalling pathway. Apc has a role in development: for example, embryos of mice with truncated Apc do not complete gastrulation. To understand this role more fully, we examined the effect of truncated Apc on zebrafish development. Here we show that, in contrast to mice, zebrafish do complete gastrulation. However, mutant hearts fail to loop and form excessive endocardial cushions. Conversely, overexpression of Apc or Dickkopf 1 (Dkk1), a secreted Wnt inhibitor, blocks cushion formation. In wild-type hearts, nuclear beta-catenin, the hallmark of activated canonical Wnt signalling, accumulates only in valve-forming cells, where it can activate a Tcf reporter. In mutant hearts, all cells display nuclear beta-catenin and Tcf reporter activity, while valve markers are markedly upregulated. Concomitantly, proliferation and epithelial-mesenchymal transition, normally restricted to endocardial cushions, occur throughout the endocardium. Our findings identify a novel role for Wnt/beta-catenin signalling in determining endocardial cell fate.",

author = "A.F. Hurlstone and A.P. Haramis and E. Wienholds and H.L. Begthel and J. Korving and {van Eeden}, F. and E. Cuppen and D. Zivkovic and R. Plasterk and J.C. Clevers",

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doi = "10.1038/nature02028",

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T1 - The Wnt/beta-catenin pathway regulates cardiac valve formation

AU - Hurlstone, A.F.

AU - Haramis, A.P.

AU - Wienholds, E.

AU - Begthel, H.L.

AU - Korving, J.

AU - van Eeden, F.

AU - Cuppen, E.

AU - Zivkovic, D.

AU - Plasterk, R.

AU - Clevers, J.C.

N1 - Reporting year: 2003 Metis note: 14534590

PY - 2003

Y1 - 2003

N2 - Truncation of the tumour suppressor adenomatous polyposis coli (Apc) constitutively activates the Wnt/beta-catenin signalling pathway. Apc has a role in development: for example, embryos of mice with truncated Apc do not complete gastrulation. To understand this role more fully, we examined the effect of truncated Apc on zebrafish development. Here we show that, in contrast to mice, zebrafish do complete gastrulation. However, mutant hearts fail to loop and form excessive endocardial cushions. Conversely, overexpression of Apc or Dickkopf 1 (Dkk1), a secreted Wnt inhibitor, blocks cushion formation. In wild-type hearts, nuclear beta-catenin, the hallmark of activated canonical Wnt signalling, accumulates only in valve-forming cells, where it can activate a Tcf reporter. In mutant hearts, all cells display nuclear beta-catenin and Tcf reporter activity, while valve markers are markedly upregulated. Concomitantly, proliferation and epithelial-mesenchymal transition, normally restricted to endocardial cushions, occur throughout the endocardium. Our findings identify a novel role for Wnt/beta-catenin signalling in determining endocardial cell fate.

AB - Truncation of the tumour suppressor adenomatous polyposis coli (Apc) constitutively activates the Wnt/beta-catenin signalling pathway. Apc has a role in development: for example, embryos of mice with truncated Apc do not complete gastrulation. To understand this role more fully, we examined the effect of truncated Apc on zebrafish development. Here we show that, in contrast to mice, zebrafish do complete gastrulation. However, mutant hearts fail to loop and form excessive endocardial cushions. Conversely, overexpression of Apc or Dickkopf 1 (Dkk1), a secreted Wnt inhibitor, blocks cushion formation. In wild-type hearts, nuclear beta-catenin, the hallmark of activated canonical Wnt signalling, accumulates only in valve-forming cells, where it can activate a Tcf reporter. In mutant hearts, all cells display nuclear beta-catenin and Tcf reporter activity, while valve markers are markedly upregulated. Concomitantly, proliferation and epithelial-mesenchymal transition, normally restricted to endocardial cushions, occur throughout the endocardium. Our findings identify a novel role for Wnt/beta-catenin signalling in determining endocardial cell fate.

U2 - 10.1038/nature02028

DO - 10.1038/nature02028

M3 - Article

SN - 0028-0836

VL - 425

SP - 633

EP - 637

JO - Nature

JF - Nature

IS - 6958

ER -

The Wnt/beta-catenin pathway regulates cardiac valve formation

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