Distinctive Roles of Canonical and Noncanonical Wnt Signaling in Human Embryonic Cardiomyocyte Development

Silvia Mazzotta, Carlos Neves, Rory J Bonner, Andreia S Bernardo, Kevin Docherty, Stefan Hoppler

Research output: Contribution to journalArticle

25 Citations (Scopus)
5 Downloads (Pure)

Abstract

Wnt signaling is a key regulator of vertebrate heart development; however, specific roles for human cardiomyocyte development remain uncertain. Here we use human embryonic stem cells (hESCs) to analyze systematically in human cardiomyocyte development the expression of endogenous Wnt signaling components, monitor pathway activity, and dissect stage-specific requirements for canonical and noncanonical Wnt signaling mechanisms using small-molecule inhibitors. Our analysis suggests that WNT3 and WNT8A, via FZD7 and canonical signaling, regulate BRACHYURY expression and mesoderm induction; that WNT5A/5B, via ROR2 and noncanonical signaling, regulate MESP1 expression and cardiovascular development; and that later in development WNT2, WNT5A/5B, and WNT11, via FZD4 and FZD6, regulate functional cardiomyocyte differentiation via noncanonical Wnt signaling. Our findings confirm in human development previously proposed roles for canonical Wnt signaling in sequential stages of vertebrate cardiomyogenesis, and identify more precise roles for noncanonical signaling and for individual Wnt signal and Wnt receptor genes in human cardiomyocyte development.

Original languageEnglish
Pages (from-to)764-776
Number of pages13
JournalStem Cell Reports
Volume7
Issue number4
Early online date15 Sep 2016
DOIs
Publication statusPublished - 11 Oct 2016

Fingerprint

Human Development
Cardiac Myocytes
Embryonic Development
Vertebrates
Wnt Receptors
Mesoderm
Stem cells
Genes
Molecules

Cite this

Distinctive Roles of Canonical and Noncanonical Wnt Signaling in Human Embryonic Cardiomyocyte Development. / Mazzotta, Silvia; Neves, Carlos; Bonner, Rory J; Bernardo, Andreia S; Docherty, Kevin; Hoppler, Stefan.

In: Stem Cell Reports, Vol. 7, No. 4, 11.10.2016, p. 764-776.

Research output: Contribution to journalArticle

Mazzotta, Silvia ; Neves, Carlos ; Bonner, Rory J ; Bernardo, Andreia S ; Docherty, Kevin ; Hoppler, Stefan. / Distinctive Roles of Canonical and Noncanonical Wnt Signaling in Human Embryonic Cardiomyocyte Development. In: Stem Cell Reports. 2016 ; Vol. 7, No. 4. pp. 764-776.
@article{d0626aabd2694acebddc701148c191df,
title = "Distinctive Roles of Canonical and Noncanonical Wnt Signaling in Human Embryonic Cardiomyocyte Development",
abstract = "Wnt signaling is a key regulator of vertebrate heart development; however, specific roles for human cardiomyocyte development remain uncertain. Here we use human embryonic stem cells (hESCs) to analyze systematically in human cardiomyocyte development the expression of endogenous Wnt signaling components, monitor pathway activity, and dissect stage-specific requirements for canonical and noncanonical Wnt signaling mechanisms using small-molecule inhibitors. Our analysis suggests that WNT3 and WNT8A, via FZD7 and canonical signaling, regulate BRACHYURY expression and mesoderm induction; that WNT5A/5B, via ROR2 and noncanonical signaling, regulate MESP1 expression and cardiovascular development; and that later in development WNT2, WNT5A/5B, and WNT11, via FZD4 and FZD6, regulate functional cardiomyocyte differentiation via noncanonical Wnt signaling. Our findings confirm in human development previously proposed roles for canonical Wnt signaling in sequential stages of vertebrate cardiomyogenesis, and identify more precise roles for noncanonical signaling and for individual Wnt signal and Wnt receptor genes in human cardiomyocyte development.",
author = "Silvia Mazzotta and Carlos Neves and Bonner, {Rory J} and Bernardo, {Andreia S} and Kevin Docherty and Stefan Hoppler",
note = "Open Access funded by British Heart Foundation Under a Creative Commons license Acknowledgments Our thanks go to Gioia Polidori Francisco for training and discussions, Kate Watt and Yvonne Turnbull for technical and laboratory managerial support, Kadri Oras and Laura Ferguson for experimental support, Po-Lin So and Bruce Conklin (Gladstone Institutes) for providing their unpublished protocols, and Yukio Nakamura for discussion. This research is supported by the British Heart Foundation (PG/12/75/29851) and the Institute of Medical Sciences. A.S.B. was supported by the British Heart Foundation (FS/12/37/29516).",
year = "2016",
month = "10",
day = "11",
doi = "10.1016/j.stemcr.2016.08.008",
language = "English",
volume = "7",
pages = "764--776",
journal = "Stem Cell Reports",
issn = "2213-6711",
publisher = "Cell Press",
number = "4",

}

TY - JOUR

T1 - Distinctive Roles of Canonical and Noncanonical Wnt Signaling in Human Embryonic Cardiomyocyte Development

AU - Mazzotta, Silvia

AU - Neves, Carlos

AU - Bonner, Rory J

AU - Bernardo, Andreia S

AU - Docherty, Kevin

AU - Hoppler, Stefan

N1 - Open Access funded by British Heart Foundation Under a Creative Commons license Acknowledgments Our thanks go to Gioia Polidori Francisco for training and discussions, Kate Watt and Yvonne Turnbull for technical and laboratory managerial support, Kadri Oras and Laura Ferguson for experimental support, Po-Lin So and Bruce Conklin (Gladstone Institutes) for providing their unpublished protocols, and Yukio Nakamura for discussion. This research is supported by the British Heart Foundation (PG/12/75/29851) and the Institute of Medical Sciences. A.S.B. was supported by the British Heart Foundation (FS/12/37/29516).

PY - 2016/10/11

Y1 - 2016/10/11

N2 - Wnt signaling is a key regulator of vertebrate heart development; however, specific roles for human cardiomyocyte development remain uncertain. Here we use human embryonic stem cells (hESCs) to analyze systematically in human cardiomyocyte development the expression of endogenous Wnt signaling components, monitor pathway activity, and dissect stage-specific requirements for canonical and noncanonical Wnt signaling mechanisms using small-molecule inhibitors. Our analysis suggests that WNT3 and WNT8A, via FZD7 and canonical signaling, regulate BRACHYURY expression and mesoderm induction; that WNT5A/5B, via ROR2 and noncanonical signaling, regulate MESP1 expression and cardiovascular development; and that later in development WNT2, WNT5A/5B, and WNT11, via FZD4 and FZD6, regulate functional cardiomyocyte differentiation via noncanonical Wnt signaling. Our findings confirm in human development previously proposed roles for canonical Wnt signaling in sequential stages of vertebrate cardiomyogenesis, and identify more precise roles for noncanonical signaling and for individual Wnt signal and Wnt receptor genes in human cardiomyocyte development.

AB - Wnt signaling is a key regulator of vertebrate heart development; however, specific roles for human cardiomyocyte development remain uncertain. Here we use human embryonic stem cells (hESCs) to analyze systematically in human cardiomyocyte development the expression of endogenous Wnt signaling components, monitor pathway activity, and dissect stage-specific requirements for canonical and noncanonical Wnt signaling mechanisms using small-molecule inhibitors. Our analysis suggests that WNT3 and WNT8A, via FZD7 and canonical signaling, regulate BRACHYURY expression and mesoderm induction; that WNT5A/5B, via ROR2 and noncanonical signaling, regulate MESP1 expression and cardiovascular development; and that later in development WNT2, WNT5A/5B, and WNT11, via FZD4 and FZD6, regulate functional cardiomyocyte differentiation via noncanonical Wnt signaling. Our findings confirm in human development previously proposed roles for canonical Wnt signaling in sequential stages of vertebrate cardiomyogenesis, and identify more precise roles for noncanonical signaling and for individual Wnt signal and Wnt receptor genes in human cardiomyocyte development.

U2 - 10.1016/j.stemcr.2016.08.008

DO - 10.1016/j.stemcr.2016.08.008

M3 - Article

VL - 7

SP - 764

EP - 776

JO - Stem Cell Reports

JF - Stem Cell Reports

SN - 2213-6711

IS - 4

ER -