Wnt5a and Wnt11 are essential for second heart field progenitor development

Cohen, Ethan David; Miller, Mayumi F.; Wang, Zichao; Moon, Randall T.; Morrisey, Edward E.

doi:10.1242/dev.069377

Cited by 131 publications

(138 citation statements)

References 61 publications

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“…3A-C). This malformation may lead to embryonic lethality and confirmed the findings of a recent study (Cohen et al, 2012). Nkx2.5, a homeobox transcriptional regulator that is essential for heart looping (Lyons et al, 1995), was expressed throughout the myocardial layer of the heart tube in control embryos at E9.5 (Fig.…”

Section: Wnt11supporting

confidence: 90%

Wnt5aandWnt11regulate mammalian anterior-posterior axis elongation

et al. 2015

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Mesoderm formation and subsequent anterior-posterior (A-P) axis elongation are fundamental aspects of gastrulation, which is initiated by formation of the primitive streak (PS). Convergent extension (CE) movements and epithelial-mesenchymal transition (EMT) are important for A-P axis elongation in vertebrate embryos. The evolutionarily conserved planar cell polarity (PCP) pathway regulates CE, and Wnts regulate many aspects of gastrulation including CE and EMT. However, the Wnt ligands that regulate A-P axis elongation in mammalian development remain unknown. Wnt11 and Wnt5a regulate axis elongation in lower vertebrates, but only Wnt5a, not Wnt11, regulates mammalian PCP signaling and A-P axis elongation in development. Here, by generating Wnt5a; Wnt11 compound mutants, we show that Wnt11 and Wnt5a play redundant roles during mouse A-P axis elongation. Both genes regulate trunk notochord extension through PCP-controlled CE of notochord cells, establishing a role for Wnt11 in mammalian PCP. We show that Wnt5a and Wnt11 are required for proper patterning of the neural tube and somites by regulating notochord formation, and provide evidence that both genes are required for the generation and migration of axial and paraxial mesodermal precursor cells by regulating EMT. Axial and paraxial mesodermal precursors ectopically accumulate in the PS at late gastrula stages in Wnt5a −/− ; Wnt11−/− embryos and these cells ectopically express epithelial cell adhesion molecules. Our data suggest that Wnt5a and Wnt11 regulate EMT by inducing p38 (Mapk14) phosphorylation. Our findings provide new insights into the role of Wnt5a and Wnt11 in mouse early development and also in cancer metastasis, during which EMT plays a crucial role.

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Section: Wnt11supporting

confidence: 90%

Wnt5aandWnt11regulate mammalian anterior-posterior axis elongation

et al. 2015

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“…For example, stromal cells that support the intestinal stem cell niche express at least six different Wnts at the same time (Kabiri et al, 2014). While in isolated instances, specific Wnt pairs have been shown to combine to enhance β-catenin signaling during embryonic development, whether this is a general phenomenon remains unclear (Cha et al, 2008;Cohen et al, 2012;Miller et al, 2012). Notably, increased expression of multiple Wnt ligands has been described in a number of cancers (Akiri et al, 2009;Bafico et al, 2004;Benhaj et al, 2006;Suzuki et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Wnt proteins synergize to activate β-catenin signaling

Alok

Lei

Jagannathan

et al. 2017

Journal of Cell Science

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Wnt ligands are involved in diverse signaling pathways that are active during development, maintenance of tissue homeostasis and in various disease states. While signaling regulated by individual Wnts has been extensively studied, Wnts are rarely expressed alone, and the consequences of Wnt gene co-expression are not well understood. Here, we studied the effect of co-expression of Wnts on the β-catenin signaling pathway. While some Wnts are deemed 'noncanonical' due to their limited ability to activate β-catenin when expressed alone, unexpectedly, we find that multiple Wnt combinations can synergistically activate β-catenin signaling in multiple cell types. WNT1-and WNT7B-mediated synergistic Wnt signaling requires FZD5, FZD8 and LRP6, as well as the WNT7B co-receptors GPR124 (also known as ADGRA2) and RECK. Unexpectedly, this synergistic signaling occurs downstream of β-catenin stabilization, and is correlated with increased lysine acetylation of β-catenin. Wnt synergy provides a general mechanism to confer increased combinatorial control over this important regulatory pathway.

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“…β-catenin-independent) Wnt signalling mechanisms also regulate heart development (e.g. Eisenberg and Eisenberg, 1999;Pandur et al, 2002;Afouda et al, 2008;Cohen et al, 2012;Onizuka et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

sfrp1 promotes cardiomyocyte differentiation in Xenopus via negative-feedback regulation of Wnt signalling

2013

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SUMMARYWnt signalling is a key regulator of vertebrate heart development, yet it is unclear which specific Wnt signalling components are required to regulate which aspect of cardiogenesis. Previously, we identified Wnt6 as an endogenous Wnt ligand required for controlling heart muscle differentiation via canonical Wnt/β-catenin signalling. Here we show for the first time a requirement for an endogenous Wnt signalling inhibitor for normal heart muscle differentiation. Expression of sfrp1 is strongly induced in differentiating heart muscle. We show that sfrp1 is not only able to promote heart muscle differentiation but is also required for the formation of normal size heart muscle in the embryo. sfrp1 is functionally able to inhibit Wnt6 signalling and its requirement during heart development relates to relieving the cardiogenesis-restricting function of endogenous wnt6. In turn, we discover that sfrp1 expression in the heart is regulated by Wnt6 signalling, which for the first time indicates that sfrp genes can function as part of a Wnt negativefeedback regulatory loop. Our experiments indicate that sfrp1 controls the size of the differentiating heart muscle primarily by regulating cell fate within the cardiac mesoderm between muscular and non-muscular cell lineages. The cardiac mesoderm is therefore not passively patterned by signals from the surrounding tissue, but regulates its differentiation into muscular and non-muscular tissue using positional information from the surrounding tissue. This regulatory network might ensure that Wnt activation enables expansion and migration of cardiac progenitors, followed by Wnt inhibition permitting cardiomyocyte differentiation.

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Wnt5a and Wnt11 are essential for second heart field progenitor development

Cited by 131 publications

References 61 publications

Wnt5aandWnt11regulate mammalian anterior-posterior axis elongation

Wnt5aandWnt11regulate mammalian anterior-posterior axis elongation

Wnt proteins synergize to activate β-catenin signaling

sfrp1 promotes cardiomyocyte differentiation in Xenopus via negative-feedback regulation of Wnt signalling

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