Wnt Signaling in Heart Organogenesis

Hoppler, Stefan; Mazzotta, Silvia; Kühl, Michael

doi:10.1002/9781118444122.ch22

Cited by 8 publications

(13 citation statements)

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“…Our molecular understanding of noncanonical WNT signaling is still rudimentary, and methods for monitoring noncanonical Wnt signaling activity are therefore less well established; specifically, there is no reliable pathway indicator gene for noncanonical WNT signaling. Since a JNK-dependent Wnt pathway is prominent during heart development ( Gessert and Kühl, 2010 , Hoppler et al., 2014 ), we monitored expression of the recently identified target gene of noncanonical Wnt/JNK signaling, ALCAM ( Choudhry and Trede, 2013 , Cizelsky et al., 2014 ), and protein abundance and cellular localization of phosphorylated JNK ( Pandur et al., 2002a ).…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, a vast majority of these protocols relies on experimental manipulation of Wnt signaling mechanisms (e.g., Bauwens et al., 2011 , Burridge et al., 2014 , Chen et al., 2012 , Elliott et al., 2011 , Gonzalez et al., 2011 , Hemmi et al., 2014 , Karakikes et al., 2014 , Kattman et al., 2011 , Kempf et al., 2014 , Lian et al., 2012 , Otsuji et al., 2014 , Paige et al., 2010 , Phillips et al., 2008 , Ting et al., 2014 , Yang et al., 2008 , Zhang et al., 2015 ), suggesting important roles for WNT signaling also in human heart development. However, while Wnt signaling clearly represents a key regulator of vertebrate heart development and particularly of cardiomyocyte differentiation (reviewed by Hoppler et al., 2014 ), at present there is no detailed understanding of the players and the fundamental roles of Wnt signaling at sequential developmental stages leading to human embryonic cardiomyocyte differentiation. We therefore specifically set out to test whether knowledge from animal model systems would be confirmed for human cardiomyocyte development.…”

Section: Discussionmentioning

confidence: 99%

“…In the lateral plate mesoderm (LPM) cardiac progenitor cells are induced, which can subsequently differentiate into heart muscle cells (cardiomyocytes) ( Rosenthal and Harvey, 2010 , Sylva et al., 2014 ). Wnt signaling, a well-known key regulator of vertebrate cardiomyocyte differentiation ( Hoppler et al., 2014 ), acts through several molecular mechanisms ( Hoppler and Nakamura, 2014 ): a β-catenin-dependent, so-called canonical pathway, and β-catenin-independent, so-called noncanonical pathways, among which a JNK-dependent pathway is prominent during heart development ( Gessert and Kühl, 2010 , Gessert et al., 2008 , Pandur et al., 2002a , Pandur et al., 2002b ).…”

Section: Introductionmentioning

confidence: 99%

“…Several studies in mouse and other experimental models have described diverse, and often opposing, effects of canonical and noncanonical Wnt signaling on subsequent cardiomyocyte differentiation, leading to the argument that particularly the JNK-mediated noncanonical pathway may function in this context to antagonize canonical Wnt signaling ( Abdul-Ghani et al., 2011 , Cohen et al., 2012 ; reviewed by Hoppler et al., 2014 ). In addition, canonical Wnt signaling has been shown to play multiple and conflicting roles at different stages of heart development ( Gessert and Kühl, 2010 , Naito et al., 2006 ).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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SummaryWnt 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.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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“…The WNT signaling pathway regulates patterning and morphogenesis during embryonic development and promotes tissue renewal and regeneration in adults 1,2 . Some WNT responses in vertebrates depend on a second signal provided by the R-spondin family of four secreted proteins (RSPO1-4) that drive the renewal of stem cells in many tissues 3,4 .…”

Section: Textmentioning

confidence: 99%

R-spondins can potentiate WNT signaling without LGR receptors

Lebensohn

Rohatgi

2017

Preprint

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6 2 Text 7The WNT signaling pathway regulates patterning and morphogenesis during embryonic 8 development and promotes tissue renewal and regeneration in adults 1,2 . Some WNT responses in 9 vertebrates depend on a second signal provided by the R-spondin family of four secreted proteins 10 (RSPO1-4) that drive the renewal of stem cells in many tissues 3,4 . RSPOs markedly amplify 11 target cell sensitivity to WNT ligands by neutralizing two transmembrane E3 ligases, ZNRF3 12 and RNF43, which reduce cell-surface levels of WNT receptors 5,6 . Chromosomal translocations 13 that increase RSPO expression or that inactivate ZNRF3/RNF43 can drive human cancers 7 . 14 RSPOs contain tandem furin-like repeats (FU1 and FU2), a thrombospondin type I (TSP) 15 domain, and a basic region (BR). RSPOs simultaneously engage ZNRF3/RNF43 through their 16 FU1 domain and one of three leucine-rich repeat-containing G-protein coupled receptors (LGR4-17 6) through their FU2 domain 8-12 , triggering the clearance of ZNRF3/RNF43 and the consequent 18 rise in WNT receptor levels.LGRs are selectively expressed in various tissue stem cells and are 19 considered the primary high-affinity receptors for RSPOs [13][14][15] . Using purified mutant and 20 chimeric RSPOs and cell lines lacking various receptors, we show that RSPO2 and RSPO3, but 21 not RSPO1 and RSPO4, can potentiate WNT/b-catenin signaling in the absence of all three 22

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Effective derivation of ventricular cardiomyocytes from hPSCs using ascorbic acid-containing maturation medium

Kim

Lee

et al. 2023

Animal Cells and Systems

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Cardiomyocytes derived from human pluripotent stem cells (hPSCs) can be used in various applications including disease modeling, drug safety screening, and novel cell-based cardiac therapies. Here, we report an optimized selection and maturation method to induce maturation of cardiomyocytes into a specific subtype after differentiation driven by the regulation of Wnt signaling. The medium used to optimize selection and maturation was in a glucose starvation conditions, supplemented with either a nutrition complex or ascorbic acid. Following optimized selection and maturation, more cardiac Troponin T (cTnT)-positive cardiomyocytes were detected using albumin and ascorbic acid than B27. In addition, ascorbic acid enriched maturation of ventricular cardiomyocytes. We compared cardiomyocyte-specific gene expression patterns under different selection and maturation conditions by next-generation sequencing (NGS) analysis. Our optimized conditions will enable simple and efficient maturation and specification of the desired cardiomyocyte subtype, facilitating both biomedical research and clinical applications.

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Wnt Signaling in Heart Organogenesis

Cited by 8 publications

References 80 publications

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

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

R-spondins can potentiate WNT signaling without LGR receptors

Effective derivation of ventricular cardiomyocytes from hPSCs using ascorbic acid-containing maturation medium

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