Wnt5a and Wnt11 are essential for second heart field progenitor development

Department of Medicine, Division of Endocrinology, University of Rochester, Rochester, NY 14642, USA.
Development (Impact Factor: 6.46). 06/2012; 139(11):1931-40. DOI: 10.1242/dev.069377
Source: PubMed


Wnt/β-catenin has a biphasic effect on cardiogenesis, promoting the induction of cardiac progenitors but later inhibiting their differentiation. Second heart field progenitors and expression of the second heart field transcription factor Islet1 are inhibited by the loss of β-catenin, indicating that Wnt/β-catenin signaling is necessary for second heart field development. However, expressing a constitutively active β-catenin with Islet1-Cre also inhibits endogenous Islet1 expression, reflecting the inhibitory effect of prolonged Wnt/β-catenin signaling on second heart field development. We show that two non-canonical Wnt ligands, Wnt5a and Wnt11, are co-required to regulate second heart field development in mice. Loss of Wnt5a and Wnt11 leads to a dramatic loss of second heart field progenitors in the developing heart. Importantly, this loss of Wnt5a and Wnt11 is accompanied by an increase in Wnt/β-catenin signaling, and ectopic Wnt5a/Wnt11 inhibits β-catenin signaling and promotes cardiac progenitor development in differentiating embryonic stem cells. These data show that Wnt5a and Wnt11 are essential regulators of the response of second heart field progenitors to Wnt/β-catenin signaling and that they act by restraining Wnt/β-catenin signaling during cardiac development.

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Available from: Ethan David Cohen, Nov 14, 2015
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    • "In addition, a gene set enrichment analysis revealed a functional overlap in pathways involved in embryonic heart development. Several differentially methylated genes have previously been implicated in heart development such as EGFR [105], GATA4 [106] [107] or Wnt5a [108]. However , some limitations of this study should be mentioned as the blood samples were drawn after the pregnancy and there is a lack of data on the methylation status of the infants. "
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    • "In contrast to canonical Wnt signaling, non-canonical pathway is less well characterized and its role in cardiac stem cell biology remains to be elucidated. Several studies have evidenced a positive effect of non-canonical Wnt signaling in mouse ES cell differentiation (Cohen et al., 2008), with Wnt5a and Wnt11 being requested to promote cardiac differentiation through non-canonical pathway in both the embryo and progenitor cells (Eisenberg and Eisenberg, 1999; Pandur et al., 2002; Brade et al., 2006; Palpant et al., 2007; Flaherty and Dawn, 2008; Cohen et al., 2012). "
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    • "Moreover, noncanonical Wnt pathway was also implicated in regulating SHF progenitors differentiation: loss of Wnt5a and Wnt11 affects SHF differentiation by increasing í µí»½-catenin nuclear levels [34]. The same authors [34] further showed that Wnt5a and Wnt11 are required to promote cardiogenesis and induce the expression of cardiacassociated genes in differentiating ESCs, indicating that noncanonical Wnt signaling regulates the formation of FHF and SHF associated progenitors during EBs differentiation [34]. Additionally, exogenous noncanonical Wnt2 was shown to increase cardiomyocytic differentiation from murine ESCs [35]. "
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