Wnt5a and Wnt11 are essential for second heart field progenitor development
ABSTRACT 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.
- SourceAvailable from: Stefanie Doppler
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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 , GATA4   or Wnt5a . 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. "
ABSTRACT: In many cases congenital heart disease (CHD) is represented by a complex phenotype and an array of several functional and morphological cardiac disorders. These malformations will be briefly summarized in the first part focusing on two severe CHD phenotypes, hypoplastic left heart syndrome (HLHS) and tetralogy of Fallot (TOF). In most cases of CHD the genetic origin remains largely unknown, though the complexity of the clinical picture strongly argues against a dysregulation which can be attributed to a single candidate gene but rather suggests a multifaceted polygenetic origin with elaborate interactions. Consistent with this idea, genome-wide approaches using whole exome sequencing, comparative sequence analysis of multiplex families to identify de novo mutations and global technologies to identify single nucleotide polymorphisms, copy number variants, dysregulation of the transcriptome and epigenetic variations have been conducted to obtain information about genetic alterations and potential predispositions possibly linked to the occurrence of a CHD phenotype. In the second part of this review we will summarize and discuss the available literature on identified genetic alterations linked to TOF and HLHS.Current Genomics 04/2015; 16(3). DOI:10.2174/1389202916666150303232520 · 2.87 Impact Factor
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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). "
ABSTRACT: The identification of different pools of cardiac progenitor cells resident in the adult mammalian heart opened a new era in heart regeneration as a means to restore the loss of functional cardiac tissue and overcome the limited availability of donor organs. Indeed, resident stem cells are believed to participate to tissue homeostasis and renewal in healthy and damaged myocardium although their actual contribution to these processes remain unclear. The poor outcome in terms of cardiac regeneration following tissue damage point out at the need for a deeper understanding of the molecular mechanisms controlling CPC behavior and fate determination before new therapeutic strategies can be developed. The regulation of cardiac resident stem cell fate and function is likely to result from the interplay between pleiotropic signaling pathways as well as tissue- and cell-specific regulators. Such a modular interaction-which has already been described in the nucleus of a number of different cells where transcriptional complexes form to activate specific gene programs-would account for the unique responses of cardiac progenitors to general and tissue-specific stimuli. The study of the molecular determinants involved in cardiac stem/progenitor cell regulatory mechanisms may shed light on the processes of cardiac homeostasis in health and disease and thus provide clues on the actual feasibility of cardiac cell therapy through tissue-specific progenitors.Frontiers in Physiology 07/2014; 5:219. DOI:10.3389/fphys.2014.00219 · 3.50 Impact Factor
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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 . The same authors  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 . Additionally, exogenous noncanonical Wnt2 was shown to increase cardiomyocytic differentiation from murine ESCs . "
ABSTRACT: Mammalian heart formation is a complex morphogenetic event that depends on the correct temporal and spatial contribution of distinct cell sources. During cardiac formation, cellular specification, differentiation, and rearrangement are tightly regulated by an intricate signaling network. Over the last years, many aspects of this network have been uncovered not only due to advances in cardiac development comprehension but also due to the use of embryonic stem cells (ESCs) in vitro model system. Additionally, several of these pathways have been shown to be functional or reactivated in the setting of cardiac disease. Knowledge withdrawn from studying heart development, ESCs differentiation, and cardiac pathophysiology may be helpful to envisage new strategies for improved cardiac repair/regeneration. In this review, we provide a comparative synopsis of the major signaling pathways required for cardiac lineage commitment in the embryo and murine ESCs. The involvement and possible reactivation of these pathways following heart injury and their role in tissue recovery will also be discussed.BioMed Research International 04/2014; 2014:679168. DOI:10.1155/2014/679168 · 2.71 Impact Factor