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.
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK.
authors.forename: Silvia
authors.initials: S
authors.lastname: Mazzotta
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK.
authors.forename: Carlos
authors.initials: C
authors.lastname: Neves
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK.
authors.forename: Rory J
authors.initials: RJ
authors.lastname: Bonner
authors.affiliation: The Francis Crick Institute, Mill Hill Laboratory, London NW7 1AA, UK; Anne McLaren Laboratory for Regenerative Medicine, University of Cambridge, West Forvie Building, Robinson Way, Cambridge CB2 0SZ, UK.
authors.forename: Andreia S
authors.initials: AS
authors.lastname: Bernardo
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Docherty
authors.affiliation: Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK. Electronic address: s.p.hoppler@abdn.ac.uk.
authors.forename: Stefan
authors.initials: S
authors.lastname: Hoppler
mesh_terms: D015415:Biomarkers; D002454:Cell Differentiation / Q000235:genetics; D047108:Embryonic Development / Q000235:genetics; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008648:Mesoderm / Q000196:embryology / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism*; D038081:Organogenesis; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: D015415:Biomarkers; D051176:beta Catenin; D048031:JNK Mitogen-Activated Protein Kinases