PMID:22569553

Citation	Cohen, ED, Miller, MF, Wang, Z, Moon, RT and Morrisey, EE (2012) Wnt5a and Wnt11 are essential for second heart field progenitor development. Development 139:1931-40
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.
Links	PubMed PMC3347685 Online version:10.1242/dev.069377
Keywords	Animals; Blotting, Western; Heart/embryology; Histological Techniques; Mice; Mice, Mutant Strains; Myocardium/cytology; Real-Time Polymerase Chain Reaction; Signal Transduction/physiology; Stem Cells/physiology; Wnt Proteins/metabolism; Wnt Proteins/physiology; beta Catenin/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:WNT5A		GO:0003281: ventricular septum development	ECO:0000316:	UniProtKB:P48615	P		Figure 2 A and D show both the wild type and the double mutant Wnt5a -/-;Wnt11-/- which develop a single chamber heart. It can also be seen in figure 2 B and C that the single mutants do not fully develop the ventricular septum.	complete CACAO 11215
MOUSE:WNT5A		GO:0003283: atrial septum development	ECO:0000316:	UniProtKB:P48615	P		Figure 2 A and D Hematoxylin and Eosin (H+E) staining of histological sections at E9.5 of the wild type and the double mutant Wnt5a -/-;Wnt11-/- are shown. It can be seen in the double mutant only single chamber hearts are formed from the double mutant. There is no atrial septum development in the double mutant.	complete CACAO 11216
MOUSE:WNT5A		GO:0003139: secondary heart field specification	ECO:0000316:	UniProtKB:P48615	P		Figure 3 A-D,I and Figure 4 F,G,H. Figure 3: "sections of E9.5 double-mutant, single-mutant and wild-type embryos were stained for Isl1 protein expression". "Isl1+ cells in Wnt5a–/–; Wnt11–/– embryos stained much less intensely than those in wild-type and single-mutant controls". Figure 4 F shows that when treated with Wnt5a and Wnt11, there is an increase in expression of Tbx5, Isl1, and Nkx2.5. Tbx5 is "expressed in the precardiac mesoderm and cardiac crescent before being restricted to the venous pole of the heart" and Isl1 and Nkx2.5 both mark SHF cardiac progenitors.	complete CACAO 11217
MOUSE:WNT5A		GO:0003138: primary heart field specification	ECO:0000316:	UniProtKB:P48615	P		Figure 4 E&H show the effect of recombinant Wnt5a and/or WNT11 proteins on gene expression in EBs. The expression of Mesp1 which is "expressed in early precardiac mesoderm and the cardiac crescent but later extinguished as the heart tube develops" and Nkx2.5 which "which marks both FHF and SHF cardiac progenitors" were both increased most when treated with both Wnt5a and Wnt11.	complete CACAO 11218
MOUSE:WNT5A		GO:0090082: positive regulation of heart induction by negative regulation of canonical Wnt signaling pathway	ECO:0000316:	UniProtKB:P48615	P		Figure 5 shows that Wnt5a and Wnt11 are both required to negatively regulate the canonical Wnt signaling pathway. In 5 A&B it shows that the double mutant Wnt5a-/-;Wnt11-/- shows more stained cells than the wild type controls when crossed with BAT-GAL strain Wnt reporter line and stained with X-gal. C-F shows increased expression of genes (in double mutants Wnt5a-/-;Wnt11-/-) which are upregulated by Beta-catenin signaling in the canonical wnt pathway. Figures 2&3 both show Wnt11 and Wnt5a's function as positive regulators of heart induction.	complete CACAO 11219
MOUSE:WNT11		GO:0003281: ventricular septum development	ECO:0000316:	UniProtKB:P22725	P		Figure 2 A and D: they show both the wild type and the double mutant Wnt5a -/-;Wnt11-/-. It can also be seen in figure 2 B and C that the single mutants do not fully develop the ventricular septum	complete CACAO 11159
MOUSE:WNT11		GO:0090082: positive regulation of heart induction by negative regulation of canonical Wnt signaling pathway	ECO:0000316:	UniProtKB:P22725	P		Figure 5 shows that Wnt5a and Wnt11 are both required to negatively regulate the canonical Wnt signaling pathway. In 5 A&B it shows that the double mutant Wnt5a-/-; Wnt11-/- shows more stained cells than the wild type controls when crossed with BAT-GAL strain Wnt reporter line and stained with X-gal. C-F shows increased expression of genes (in double mutants Wnt5a-/-;Wnt11-/-) which are upregulated by Beta-catenin signaling in the canonical wnt pathway. Figures 2&3 both show Wnt11 and Wnt5a's function as positive regulators of heart induction.	complete CACAO 11191
MOUSE:WNT11		GO:0003283: atrial septum development	ECO:0000316:	UniProtKB:P22725	P		Figure 2 A and D Hematoxylin and Eosin (H+E) staining of histological sections at E9.5 of the wild type and the double mutant Wnt5a -/-;Wnt11-/- are shown. It can be seen in the double mutant only single chamber hearts are formed from the double mutant. There is no atrial septum development in the double mutant.	complete CACAO 11192
MOUSE:WNT11		GO:0003138: primary heart field specification	ECO:0000316:	UniProtKB:P22725	P		Figure 4 E&H show the effect of recombinant Wnt5a and/or WNT11 proteins on gene expression in EBs. The expression of Mesp1 which is "expressed in early precardiac mesoderm and the cardiac crescent but later extinguished as the heart tube develops" and Nkx2.5 which "which marks both FHF and SHF cardiac progenitors" were both increased most when treated with both Wnt5a and Wnt11.	complete CACAO 11193
MOUSE:WNT11		GO:0003139: secondary heart field specification	ECO:0000316:	UniProtKB:P22725	P		Figure 3 A-D,I and Figure 4 F,G,H. Figure 3: "sections of E9.5 double-mutant, single-mutant and wild-type embryos were stained for Isl1 protein expression". "Isl1+ cells in Wnt5a–/–; Wnt11–/– embryos stained much less intensely than those in wild-type and single-mutant controls". Figure 4 F shows that when treated with Wnt5a and Wnt11, there is an increase in expression of Tbx5, Isl1, and Nkx2.5. Tbx5 is "expressed in the precardiac mesoderm and cardiac crescent before being restricted to the venous pole of the heart" and Isl1 and Nkx2.5 both mark SHF cardiac progenitors.	complete CACAO 11194

References

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