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Review Article | Open Access
Planar Cell Polarity Signaling Pathway in Congenital Heart Diseases
Congenital heart disease (CHD) is a common cardiac disorder in humans. Despite many advances in the understanding of CHD and the identification of many associated genes, the fundamental etiology for the majority of cases remains unclear. The planar cell polarity (PCP) signaling pathway, responsible for tissue polarity in Drosophila and gastrulation movements and cardiogenesis in vertebrates, has been shown to play multiple roles during cardiac differentiation and development. The disrupted function of PCP signaling is connected to some CHDs. Here, we summarize our current understanding of how PCP factors affect the pathogenesis of CHD.
Congenital heart disease (CHD), the most common disorder of congenital disease in humans, occurs in approximately 1% of live births [1, 2]. Among many types of CHDs, septation and alignment defects make up the largest group of CHDs, including ventricular and atrial septal defects, tetralogy of Fallot, and double-outlet right ventricle defects . In particular, congenital defects that involve the outflow tract are especially prevalent, including defects of the transposition of the great arteries (TGA), double outlet right ventricle (DORV), and persistent truncus arteriosus (PTA), where a single outflow tract vessel is observed in place of the normal aorta and pulmonary artery .
The prognosis, morbidity, and mortality are dependent on the type, size, location, number of defects, and the associated anomalies . CHD represents the cause of one-tenth of all infant deaths worldwide and is the leading noninfectious cause of death in the first year of life . Of great concern to pediatricians and cardiac surgeons are outflow tract defects, because babies that suffer from these problems typically require urgent and complex surgeries shortly after birth.
In recent years, a correlation has been made between dysregulation of the planar cell polarity signaling pathway and CHD.
2. Cardiac Development
2.1. Early Heart Development
In vertebrates, the heart is the first organ to form and has a vital role in the distribution of nutrients and oxygen in the embryo . Formation of the vertebrate heart can be subdivided into distinct but partially overlapping phases, such as specification of cardiac progenitors and the formation of the linear heart tube by cell migration and morphogenetic movements, followed by cardiac looping, chamber formation, septation, and maturation .
Myocardial cells are derived from the mesoderm, which emerge from the primitive streak during gastrulation. Later, these cells migrate from the streak in an anterior-lateral direction to positions under the headfolds forming two groups of cells on either side of the midline . The cells then extend across the midline to develop a crescent-shaped epithelium called the cardiac crescent, which fuses at the midline to form the early heart tube  called the primary heart field or the first heart field (FHF). These cells will form the left ventricle.
During the formation of a mature heart, the linear heart tube subsequently expands. This is achieved by two mechanisms: cell proliferation and recruitment of additional cells. The latter cells originate in the second heart field (SHF) a cardiac precursor cell population distinct from the first heart field . SHF will mainly develop into the outflow tract (OFT) and the right ventricle, but also into both atria . Also, as demonstrated in the chicken system, cells of the SHF populate the right ventricle . Frog hearts contain a single ventricle; therefore, cells of the SHF exclusively end up in the OFT .
2.2. Outflow Tract Formation
OFT formation involves interactions between diverse cell types in the region of the pharyngeal splanchnic mesenchyme and in SHF that gives rise to the myocardium of the OFT and its endothelial lining [14, 15]. Cardiac neural crest (CNC) cell-derived mesenchyme also plays an important role . These cells form the greater part of the outflow tract cushions, and if they are removed physically or genetically, then outflow tract septation fails [17, 18].
OFT is normally divided by the fusion of a series of ridges or cushions within itself. There are two mechanisms. In the early stages, the dominant mechanism is myocardialization . First during myocardialization, the cells within the thin layer of OFT myocardium fail to adhere to one another tightly. Then, the cells stop behaving like an epithelium and, instead, show protrusive activity and move into the adjacent outflow tract cushions. Thus, the cushions become directly populated by cardiomyocytes . It is thought that myocardialization shares characteristics with the convergent and extension (CE) process, at least with respect to the polarized migration of cells . Direct invasion, the second mechanism, may be complemented by the recruitment of cushion mesenchymal cells into the muscle lineage .
3. The Planar Cell Polarity Signaling Pathway
Signaling by ligands of the Wnt family, which controls cell proliferation and patterning, is important for a variety of crucial cell changes and morphogenetic events in development. Two branches of the Wnt pathway exist: a β-catenin-dependent canonical pathway and β-catenin-independent noncanonical pathways [22, 23]. Noncanonical Wnt signaling has been shown to be inhibitory for canonical Wnt signaling through multiple mechanisms . In zebrafish, Wnt genes that activate the noncanonical Wnt pathway are pipetail/Wnt5  and silberblick/Wnt11 .
Noncanonical Wnt pathways, also called the planar cell polarity (PCP) signaling pathway, work on planar cell polarity in Drosophila and gastrulation movements and cardiogenesis in vertebrates [27–29].
PCP signaling involves a multiprotein complex that associates at the cell membrane. This complex involves the core proteins Frizzled (Fz), Dishevelled (Dvl), Prickle (Pk), Vangl/Strabismus (Vangl), Celsr/Flamingo (Celsr), and Diego (Dgo). In addition, Scribble (Scrib) [30, 31] and Ptk7  are also regarded as the PCP proteins. Formation of the multiprotein complex is thought to modulate the pathway, rather than the components being members of a linear pathway. Vang/Pk are thought to antagonize Fz/Dvl signaling . PCP pathways are important in polarized cell migration and organ morphogenesis through activation of cytoskeletal pathways, such as those involving the small GTPases RhoA and cdc42, Rho kinase (ROCK), protein kinase C (PKC), and Jun N-terminal kinase (JNK) [4, 22].
Molecules involved in the PCP pathway commonly fall into 1 of these 3 categories: (1) the “upstream” factors in charge of the coordination of the planar polarity across the whole tissue (i.e., some atypical cadherins like Dachsous and Fat ); (2) the so-called “core polarity genes” that provide intrinsic polarization cues within single cells through their uneven subcellular localization; and (3) the tissue-specific factors needed for the emergence of the polarized structures characteristic of each cell type [34, 35].
4. Planar Cell Polarity Signaling Pathway in CHD
Normal cardiac development is dependent on PCP signaling [3, 20, 36, 37], which contributes to correct cardiac specification in the mesodermal germ layer . If the correct expression of proteins in PCP signaling is disrupted, then defects may be seen in the heart.
4.1. Vang-Like 2
Vertebrates have two Vang-like (Vangl) genes, Vangl1 and Vangl2, which are homologs of the Drosophila gene Van Gogh/Strabismus (Vang/Stbm). Vang mutations disrupt the organization of various epithelial structures, causing characteristic swirled patterns of hairs on wing cells and disorientation of eye ommatidia . Vangl1 and Vangl2 proteins share ~70% sequence similarity, which underlies their conserved functions: Vangl1 and Vangl2 proteins bind to three mammalian Dvl proteins, and Lp mutations engineered in Vangl1 or Vangl2 abrogate interaction with Dvl . The Vangl2 gene encodes a membrane protein comprising four transmembrane domains and a large intracellular domain with a PDZ-domain-binding motif at its carboxy terminus . Mutations in Vangl2 can cause neural tube defects and cardiac abnormalities . Loop-tail (Lp), a naturally occurring mouse mutant, develops severe cardiovascular defects in association with abnormal midline development [40, 42], and is often used when studying of Vangl2.
4.2. Outflow Tract
Vangl2 plays an important role in the development of the outflow tract for the following reasons: Vangl2 is strongly expressed in the outflow tract myocardium, including the cells that migrate into the outflow tract cushions . Conspicuous abnormalities are found in the outflow trace of Lp mutants , and similarities exist between myocardialization of the OFT and the CE movement during gastrulation, in which Vangl2 is generally thought to be correlated .
Complex cardiovascular defects can be found in Lp homozygotes, including double-outlet right ventricle defects, with obligatory peri-membrane ventricular septal defects, and double-sided aortic arch defects, with associated abnormalities in the aortic arch arteries . During the myocardialization of the Lp mice, both the extension of polarized membrane protrusions and the reorganization of the actin cytoskeleton are inhibited in myocardial cells at the muscle-cushion tissue, strongly suggesting that this is a defect in cell polarity and/or cell movement, rather than some other aspect of cell behavior . RhoA and ROCK1 , the downstream mediators of the PCP signaling pathway, are required as well for Vangl2 function . However, the Tetralogy of Fallot (ToF) abnormality, resulting from disturbances of morphogenetic processes in OFT development , does not show any specific mutations in Vangl2 gene that are responsible for the ToF phenotype . Further research could include the possible role of other PCP components expressed in the development of the outflow tract . Furthermore, a typical PCP phenotype in a mouse mutant for the Sec24b gene has been reported, including abnormally small ventricles and abnormally arranged OFT vessels . Sec24b is a component of the coat protein complex II (COPII) that is essential for intracellular endoplasmic-reticulum- (ER-) to-Golgi protein transport . In Sec24b mutation mice, both abnormal Vangl2 expression or localization were detected; however, this abnormal expression or localization of Vangl2 may only be partially responsible for the Sec24b mutation caused cardiac defects .
As for Vangl1, its role in OFT is much smaller than Vangl2. No cardiac outflow abnormalities were detected in Vangl1gt/+, Vangl2lp/+ double heterozygotes, or in Vanglgt/gt homozygotes, only an aberrant right subclavian artery was found in the former, suggesting that the two genes genetically interact to regulate the proper development of the extra-cardiac structures .
4.3. Coronary Circulation
The coronary arteries that channel oxygen rich blood throughout the ventricular myocardium are formed from cells that originally derive from a region of the splanchnic mesoderm known as the proepicardium [48, 49]. Vangl2-PCP signaling can play a noncell autonomous role in coronary artery formation . For example, in the animals with Lp/Lp hearts, the coronary vessels fail to develop a normal smooth muscle cell layer and instead develop enlarged ectopic vessels in the subepicardium. Reduced fibronectin deposition, because of loss of functional vangl2 in the subepicardial space, is associated with limited migration of epicardially derived cells (EPDCs) into the ventricular myocardium and likely contributes to those defects . Fibronectin deposition has also been shown to be deficient at tissue boundaries in Xenopus embryos in which Vangl2 is disrupted and PCP signaling is abnormal [51, 52]. These defects were associated with defects in the polarized cell movements during the process of CE, which resembles the Lp/Lp heart, where fibronectin deposition is reduced at the epicardial-myocardial boundary and cell migration is impaired .
Similarly, mice deficient in connexin 43 also have defects in epicardial cell polarization, migration, and early remodeling of the coronary vascular plexus [53, 54]. However, aberrant expression of planar cell polarity pathway components was not detected in the connexin 43 knockout hearts, so it is currently unclear whether and how connexin 43 interacts with the planar cell polarity pathway .
The vertebrate ankyrin repeat protein, Diversin, is related to the Drosophila protein Diego, which controls PCP during fly development . Diversin also acts in the canonical Wnt signaling pathway, where its centrosomal localization is crucial for its function in Wnt signaling . Diversin is a modular protein containing N-terminal ankyrin repeats, a central casein kinase-binding domain, and a C-terminal domain that binds axin/conductin .
Early zebrafish embryos injected with Diversin mRNA that encodes a protein lacking the ankyrin repeat domain, Div-ΔANK, were found to develop cardiac bifida ; however, those cardiac bifida can be rescued by coinjection of an activated form of RhoA (RhoA-V14), suggesting that Diversin controls heart formation through RhoA . Cardiac bifida in fish is generated when the bilateral heart anlagen fail to fuse because of defective migration of myocardial precursors to the dorsal midline [60, 61], which is regulated by PCP signaling . These results suggest that Diversin can play a role in heart through PCP in the downstream of RhoA.
Meanwhile, Diversin and Dishevelled are accepted as mutually dependent players within the PCP signaling pathway. The Diversin orthologue of Drosophila, Diego, genetically interacts with and physically binds to Dishevelled . However, during cardiogenesis, coinjection of both dominant-negative molecules, Div-ΔANK and Dvl-ΔDEP, did not synergize, suggesting that both Diversin and Dishevelled control heart formation and PCP signaling in zebrafish embryogenesis by similar mechanisms .
In the inv/inv mouse, carrying an insertional mutation in the inversin gene, some cardiopulmonary malformations were found, which are not rare in the mutant mice. The inv/inv mice have a propensity for defects in the development of the right ventricular OFT and the interventricular septum.
Dishevelled (dsh in Drosophila or Dvl in mice) proteins, of which three have been identified in humans and mice, are highly conserved components of both the canonical Wnt pathway , and the PCP pathway . They function as essential scaffolding proteins that interact with diverse proteins, including kinases, phosphatases, and adaptor proteins [65, 66].
In zebrafish, it is reported that injection of the dominant-negative Dishevelled lacking the DEP domain (Dvl-ΔDEP) into zebrafish embryos induced cardiac bifida phenotypes and CE defects. Dishevelled regulates heart formation via the activation of RhoA. Meanwhile, during cardiogenesis, Div-ΔANK and Dvl-ΔDEP, the frequency of cardiac bifida was not increased .
In mice, mutations in the Dvl2 gene, one of three vertebrate homologues of Drosophila Dishevelled, developed OFT defects similar to those seen in Lp mice, including double-outlet right ventricle and ventricular septal defects . Dvl1/Dvl2 double mutants develop the neural tube defect craniorachischisis , which is associated with disruption of PCP signaling in mice . Since both Vangl2 and Dvl2 are expressed in the OFT myocardium , Dvl2 is suggested to act in PCP pathway in OFT. The PCP signaling pathway can regulate cell migration processes during gastrulation and neural crest cell migration in vertebrates [22, 67]. Dvl2 is a core PCP member in canonical Wnt signaling. But Dvl2 is also suggested to influence OFT formation through neural crest cell migration in PCP signaling since a defect is found in cardiac neural crest development during OFT formation in Dvl2 null mutants .
mice died p erinatally with cardiac OFT abnormalities, and the mutants displayed a misorientated stereocilia in the organ of Corti, suggesting that Dvl3 is required for cardiac OFT development in the PCP pathway . However, OFT in mice were not due to an absence of CNC or SHF Cells. Moreover, ; mice can survive to adulthood and are fertile. In an inbred background, conotruncal abnormalities were seen, while ; hearts had similar morphologies to hearts, suggesting Dvls are functionally redundant .
4.6. Wnt5a and Wnt11
In vertebrates, Wnt5a and Wnt11 can activate the Wnt/JNK pathway, which resembles the PCP pathway in Drosophila . Wnt5a [69, 70] and Wnt11 [4, 29, 69–72] represent the PCP pathway that have been implicated in cardiogenesis.
Wnt5a primarily signals through the PCP signaling pathway, although it also has the potential to activate the canonical Wnt signaling pathway , by functioning as an antagonist of the canonical Wnts . A mutation in Wnt5a in mice can lead to PTA. In the model, Wnt5a produced in the OFT, by cells originating from the pharyngeal mesoderm, signals adjacent CNC cells during the formation of the aortopulmonary septum through a PCP pathway via localized intracellular increases in Ca2+ .
Wnt5a is thought to be supportive but not required for cardiogenesis  because in discussing Notch signaling in cardiac progenitors, Wnt5a synergizes with BMP6 and Sfrp1 to promote formation of troponin-positive cells, likely through noncanonical Wnt signaling activities. However, adding individually sFRP1, Wnt5a, and BMP6 does not significantly increase cardiac development .
Wnt11 is a secreted protein that signals through the PCP pathway and is a potent modulator of cell behavior and movement. In human, mouse, and chicken, there is a single Wnt11 gene, and in Xenopus and zebrafish, there are two, Wnt-11 and Wnt-11R . Wnt11 can activate PCP signaling and at the same time inhibit Wnt signaling . Wnt-11 shows a spatiotemporal pattern of expression that correlates with cardiac specification [76, 77] and loss-of-function experiments also demonstrated that Wnt11 is required for normal heart development and cardiac marker gene expression [29, 78]. Wnt11 leads to cardiac specification in the PCP pathway  and is conserved .
The mouse Wnt11 gene is expressed within or in close proximity to the precardiac mesoderm, and later in the myocardium of the primitive heart tube . Thus, the Wnt-11 expression domain overlaps with the first and secondary heart fields that contribute to the majority of the tissues establishing the heart [69–71, 79]. At later stages, Wnt11 is expressed in OFT, where both Wnt5a and Wnt11 signaling have morphogenetic roles [4, 16]. Interestingly, human Wnt11 has been reported to be expressed in the adult heart .
In cell culture models, Wnt11 signaling determines the fate of the cardiomyocytes and promotes differentiation of the already committed cardiomyocytes, a conclusion based in part on its capacity to induce the expression of certain cardiac transcription factor genes [29, 81–85], suggesting that Wnt11 signaling may have a broader role in the control of mammalian heart development .
5. Heart Morphogenesis
In Xenopus, Wnt11-R is expressed in neural tissue, dorsal mesenchyme derived from the dermatome region of the somites, the brachial arches, and the muscle layer of the heart, similar to the expression patterns reported for mouse and chicken Wnt11 . Inhibition of Wnt11-R function using morpholino oligomers causes defects in heart morphogenesis, in fact, 10% of the hearts exhibit a pronounced cardiac bifida phenotype, suggesting Wnt11-R functions in regulation of cardiac morphogenesis .
In cardiocytes of Xenopus, Wnt11 is required for heart formation and is sufficient to induce a contractile tissue in embryonic explants by PCP signaling which involves protein kinase C and Jun amino-terminal kinase .
When embryos injected with Wnt11-R MO on one side only were examined in section, it was clear that the myocardial layer on the injected side was thicker than on the control side. This is also visible in double-sided MO1-injected embryos. Quantitation of differentiated myocardium showed that the area of the Wnt11-R-depleted side was 26% larger than the control side .
However, in a mouse model in which Wnt-11 function has been inactivated, Wnt-11 signaling serves as a critical cell adhesion cue for the organization of the cardiomyocytes in the developing ventricular wall. In the absence of Wnt-11, the coordinated organization, intercellular contacts, colocalized expression of the cell adhesion components N-cadherin and b-catenin, and the cytoskeleton of the differentiating ventricular cardiomyocytes are all disturbed. Moreover, the ventricular wall lacking Wnt-11 signaling is thinner .
5.1. Outflow Tract
Wnt11 signaling can affect extracellular matrix composition, cytoskeletal rearrangements and polarized cell movement required for morphogenesis of the cardiac OFT . In fact, Wnt11 plays this role in the integration and crosstalk between three major signaling pathways: Wnt pathway, PCP pathway, and TGFb signaling. In Wnt11 mutants, penetrance of the outflow tract phenotype was 100% accompanied by ventricular septal defects (VSD) .
Protein tyrosine kinase 7 (Ptk7) is a transmembrane protein containing seven extracellular immunoglobulin domains and a kinase homology domain . Ptk7 is regarded as a regulator of PCP signaling that could modulate the dsh localization as well as the interaction with pathway-specific effector proteins , while someone regarded it as an essential component of PCP pathway . In Xenopus, Ptk7 is required for neural convergent extension  and can regulate neural crest migration by recruiting dishevelled (dsh) to the plasma membrane .
In chick, disruption of off-track (the chick Ptk7 homologue) causes abnormal heart development . In mouse, chuzhoi (chz) mutants, carrying a splice site mutation in Ptk7, exhibit several defects in cardiovascular development, including OFT defects with VSD, while they exhibit minor defects in neural crest cell distribution . A genetic interaction between chuzhoi mutants and both Vangl2Lp and Celsr1Crsh mutants was demonstrated, strengthening the hypothesis that chuzhoi is involved in regulating the PCP pathway .
Scrib (also known as Scrb1) is orthologous to the Drosophila scribble gene, which regulates apical-basal polarity and functions as a tumor suppressor, regulating cell growth; scribble mutants exhibit disrupted cellular architecture [91–93]. Scrib is a putative cytoplasmic protein and is a member of the LAP protein family that is characterized by the presence of four PDZ domains. Scrib plays essential roles in cell-cell adhesion . In human, hScrib protein displays highly polarized localization in mammalian epithelial cells and could play an important role in the suppression of human tumors . Scrib has not been implicated in planar cell polarity , although some scholars identify it as PCP protein [30, 31].
In mutations in mouse Scrib (circle tail mutant, Crc), cardiac looping and chamber expansion are disrupted and abnormal development of the arterial wall and early abnormalities in myocardial organization are found. Finally, spectrum of congenital heart defects are developed, such as smaller and abnormally shaped ventricular chambers, cardiovascular defects, and atrioventricular septal defects , suggesting that Crc can develop heart malformations and cardiomyopathy attributable to abnormalities in cardiomyocyte organization within the early heart tube .
The mechanism of Scrib involved in heart development may refer to N-cadherin. The integrity of the heart tube is dependent on N-cadherin, which is tightly localized to the lateral membranes of cardiomyocytes from the earliest time of heart tube formation . The N-cadherin zebrafish mutant can develop a disorganized myocardium with abnormally shaped and loosely-aggregated cardiomyocytes , which is very similar to Crc. Scrib is required for the correct localization of N-cadherin and β-catenin at the lateral cell membrane in the primitive myocardium .
Moreover, Scrib and Vangl2 can interact in heart development. Scrib is required for the correct localization of Vangl2 within the membrane compartments of cardiomyocytes and that Scrib is acting to direct the PCP pathway in the developing myocardium. Double heterozygosity for mutations in both Scrib and Vangl2 can cause cardiac defects similar to those found in homozygous mutants for each gene but without other major defects. Those are in accord with the fact  that proteins interact physically through discrete PDZ-binding domains, observed in yeast 2 hybrid and coimmunoprecipitation studies , in addition, heterozygotes (Lp/+,Crc/+) also exhibit craniorachischisis, which is equal in severity to either Crc/Crc or Lp/Lp mice , suggesting the overlapping expression of Scrb1 with Vangl2.
The planar cell polarity (PCP) pathway is a highly conserved signaling pathway that mediates changes in cell polarity and cell motility during cardiogenesis, through activation of cytoskeletal pathways, such as RhoA and Rho kinase (ROCK). Several components of the pathway are expressed within the developing heart, and the disrupted function of pathway members in chick, Xenopus, zebrafish, and mouse are associated with some heart defect, which leads to congenital heart disease (CHD). The interaction of proteins within the PCP pathway and the intercross of the PCP pathway with the other pathways such as the Wnt signaling pathway are also demonstrated. No genes within the PCP pathway that cause cardiovascular defects in humans have been described thus far.
|PCP:||Planar cell polarity|
|CHD:||Congenital heart disease|
|FHF:||First heart field|
|SHF:||Second heart field|
|CNC:||Cardiac neural crest|
|CE:||Convergent and extension|
|EPDCs:||Epicardially derived cells.|
This work was supported by National Science Foundation of China (no. 30825039, no. 31171020, and no. 30973236 to Dezhi Mu; no. 30872545 and no. 81070136 to Yimin Hua), and Program of Changjiang Scholars and Innovative Research Team in University (IRT0935). Gang Wu and Jiao Ge contributed equally to the study.
- S. M. Reamon-Buettner, K. Spanel-Borowski, and J. Borlak, “Bridging the gap between anatomy and molecular genetics for an improved understanding of congenital heart disease,” Annals of Anatomy, vol. 188, no. 3, pp. 213–220, 2006.
- M. D. Reller, M. J. Strickland, T. Riehle-Colarusso, W. T. Mahle, and A. Correa, “Prevalence of congenital heart defects in metropolitan atlanta, 1998–2005,” Journal of Pediatrics, vol. 153, no. 6, pp. 807–813, 2008.
- D. J. Henderson, S. J. Conway, N. D. E. Greene et al., “Cardiovascular defects associated with abnormalities in midline development in the Loop-tail mouse mutant,” Circulation Research, vol. 89, no. 1, pp. 6–12, 2001.
- W. Zhou, L. Lin, A. Majumdar et al., “Modulation of morphogenesis by noncanonical Wnt signaling requires ATF/CREB family-mediated transcriptional activation of TGFβ2,” Nature Genetics, vol. 39, no. 10, pp. 1225–1234, 2007.
- H. S. Khalil, A. M. Saleh, and S. N. Subhani, “Maternal obesity and neonatal congenital cardiovascular defects,” International Journal of Gynecology and Obstetrics, vol. 102, no. 3, pp. 232–236, 2008.
- J.-B. Huang, Y.-L. Liu, and X.-D. Lv, “Pathogenic mechanisms of congenital heart disease,” Fetal and Pediatric Pathology, vol. 29, no. 5, pp. 359–372, 2010.
- M. Buckingham, S. Meilhac, and S. Zaffran, “Building the mammalian heart from two sources of myocardial cells,” Nature Reviews Genetics, vol. 6, no. 11, pp. 826–837, 2005.
- S. Gessert and M. Kühl, “The multiple phases and faces of Wnt signaling during cardiac differentiation and development,” Circulation Research, vol. 107, no. 2, pp. 186–199, 2010.
- P. P. L. Tam, M. Parameswaran, S. J. Kinder, and R. P. Weinberger, “The allocation of epiblast cells to the embryonic heart and other mesodermal lineages: the role of ingression and tissue movement during gastrulation,” Development, vol. 124, no. 9, pp. 1631–1642, 1997.
- A. F. M. Moorman, V. M. Christoffels, R. H. Anderson, and M. J. B. van den Hoff, “The heart-forming fields: one or multiple?” Philosophical Transactions of the Royal Society B, vol. 362, no. 1484, pp. 1257–1265, 2007.
- C. L. Cai, X. Liang, Y. Shi et al., “Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart,” Developmental Cell, vol. 5, no. 6, pp. 877–889, 2003.
- M. S. Rana, N. C. A. Horsten, S. Tesink-Taekema, W. H. Lamers, A. F. M. Moorman, and M. J. B. van den Hoff, “Trabeculated right ventricular free wall in the chicken heart forms by ventricularization of the myocardium initially forming the outflow tract,” Circulation Research, vol. 100, no. 7, pp. 1000–1007, 2007.
- S. Gessert and M. Kühl, “Comparative gene expression analysis and fate mapping studies suggest an early segregation of cardiogenic lineages in Xenopus laevis,” Developmental Biology, vol. 334, no. 2, pp. 395–408, 2009.
- D. Srivastava and E. N. Olson, “A genetic blueprint for cardiac development,” Nature, vol. 407, no. 6801, pp. 221–226, 2000.
- K. R. Chien, “Myocyte survival pathways and cardiomyopathy: implications for trastuzumab cardiotoxicity,” Seminars in Oncology, vol. 27, no. 6, pp. 9–14, 2000.
- J. R. Schleiffarth, A. D. Person, B. J. Martinsen et al., “Wnt5a is required for cardiac outflow tract septation in mice,” Pediatric Research, vol. 61, no. 4, pp. 386–391, 2007.
- M. L. Kirby, T. F. Gale, and D. E. Stewart, “Neural crest cells contribute to normal aorticopulmonary septation,” Science, vol. 220, no. 4601, pp. 1059–1061, 1983.
- V. Kaartinen, M. Dudas, A. Nagy, S. Sridurongrit, M. M. Lu, and J. A. Epstein, “Cardiac outflow tract defects in mice lacking ALK2 in neural crest cells,” Development, vol. 131, no. 14, pp. 3481–3490, 2004.
- B. P. T. Kruithof, M. J. B. van den Hoff, A. Wessels, and A. F. M. Moorman, “Cardiac muscle cell formation after development of the linear heart tube,” Developmental Dynamics, vol. 227, no. 1, pp. 1–13, 2003.
- D. J. Henderson, H. M. Phillips, and B. Chaudhry, “Vang-like 2 and noncanonical Wnt signaling in outflow tract development,” Trends in Cardiovascular Medicine, vol. 16, no. 2, pp. 38–45, 2006.
- B. P. T. Kruithof, M. J. B. van den Hoff, S. Tesink-Taekema, and A. F. M. Moorman, “Recruitment of intra- and extracardiac cells into the myocardial lineage during mouse development,” Anatomical Record, Part A, vol. 271, no. 2, pp. 303–314, 2003.
- M. T. Veeman, J. D. Axelrod, and R. T. Moon, “A second canon: functions and mechanisms of β-catenin-independent Wnt signaling,” Developmental Cell, vol. 5, no. 3, pp. 367–377, 2003.
- C. Y. Logan and R. Nusse, “The Wnt signaling pathway in development and disease,” Annual Review of Cell and Developmental Biology, vol. 20, pp. 781–810, 2004.
- P. Maye, J. Zheng, L. Li, and D. Wu, “Multiple mechanisms for Wnt11-mediated repression of the canonical Wnt signaling pathway,” Journal of Biological Chemistry, vol. 279, no. 23, pp. 24659–24665, 2004.
- B. Kilian, H. Mansukoski, F. C. Barbosa, F. Ulrich, M. Tada, and C. P. Heisenberg, “The role of Ppt/Wnt5 in regulating cell shape and movement during zebrafish gastrulation,” Mechanisms of Development, vol. 120, no. 4, pp. 467–476, 2003.
- C.-P. Heisenberg, M. Tada, G. J. Rauch et al., “Silberblick/Wnt11 mediates convergent extension movements during zebrafish gastrulation,” Nature, vol. 405, no. 6782, pp. 76–81, 2000.
- T. J. Klein and M. Mlodzik, “Planar cell polarization: an emerging model points in the right direction,” Annual Review of Cell and Developmental Biology, vol. 21, pp. 155–176, 2005.
- T. Matsui, A. Raya, Y. Kawakami et al., “Noncanonical Wnt signaling regulates midline convergence of organ primordia during zebrafisn development,” Genes and Development, vol. 19, no. 1, pp. 164–175, 2005.
- P. Pandur, M. Läsche, L. M. Eisenberg, and M. Kühl, “Wnt-11 activation of a non-canonical Wnt signalling pathway is required for cardiogenesis,” Nature, vol. 418, no. 6898, pp. 636–641, 2002.
- M. Montcouquiol, R. A. Rachel, P. J. Lanford, N. G. Copeland, N. A. Jenkins, and M. W. Kelley, “Identification of Vangl2 and Scrb1 as planar polarity genes in mammals,” Nature, vol. 423, no. 6936, pp. 173–177, 2003.
- E. E. Davis and N. Katsanis, “Cell polarization defects in early heart development,” Circulation Research, vol. 101, no. 2, pp. 122–124, 2007.
- V. S. Golubkov, A. V. Chekanov, P. Cieplak et al., “The Wnt/planar cell polarity protein-tyrosine kinase-7 (PTK7) is a highly efficient proteolytic target of membrane type-1 matrix metalloproteinase: implications in cancer and embryogenesis,” Journal of Biological Chemistry, vol. 285, no. 46, pp. 35740–35749, 2010.
- M. Simons and M. Mlodzik, “Planar cell polarity signaling: from fly development to human disease,” Annual Review of Genetics, vol. 42, pp. 517–540, 2008.
- J. M. Pérez-Pomares, “Myocardial-coronary interactions: against the canon,” Circulation Research, vol. 102, no. 5, pp. 513–515, 2008.
- H. Strutt and D. Strutt, “Long-range coordination of planar polarity in Drosophila,” BioEssays, vol. 27, no. 12, pp. 1218–1227, 2005.
- H. M. Phillips, J. N. Murdoch, B. Chaudhry, A. J. Copp, and D. J. Henderson, “Vangl2 acts via RhoA signaling to regulate polarized cell movements during development of the proximal outflow tract,” Circulation Research, vol. 96, no. 3, pp. 292–299, 2005.
- N. S. Hamblet, N. Lijam, P. Ruiz-Lozano et al., “Dishevelled 2 is essential for cardiac outflow tract development, somite segmentation and neural tube closure,” Development, vol. 129, no. 24, pp. 5827–5838, 2002.
- E. Torban, C. Kor, and P. Gros, “Van Gogh-like2 (Strabismus) and its role in planar cell polarity and convergent extension in vertebrates,” Trends in Genetics, vol. 20, no. 11, pp. 570–577, 2004.
- E. Torban, H. J. Wang, N. Groulx, and P. Gros, “Independent mutations in mouse Vangl2 that cause neural tube defects in Looptail mice impair interaction with members of the Dishevelled family,” Journal of Biological Chemistry, vol. 279, no. 50, pp. 52703–52713, 2004.
- Z. Kibar, K. J. Vogan, N. Groulx, M. J. Justice, D. A. Underhill, and P. Gros, “Ltap, a mammalian homolog of Drosophila Strabismus/Van Gogh, is altered in the mouse neural tube mutant Loop-tail,” Nature Genetics, vol. 28, no. 3, pp. 251–255, 2001.
- E. Torban, A. M. Patenaude, S. Leclerc et al., “Genetic interaction between members of the Vangl family causes neural tube defects in mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 9, pp. 3449–3454, 2008.
- Z. Kibar, S. Salem, C. Bosoi et al., “Contribution of VANGL2 mutations to isolated neural tube defects,” Clinical Genetics, vol. 80, no. 1, pp. 76–82, 2011.
- J. Shi, L. Zhang, and L. Wei, “Rho-kinase in development and heart failure: insights from genetic models,” Pediatric Cardiology, vol. 32, no. 3, pp. 297–304, 2011.
- J. P. Starr, “Tetralogy of Fallot: yesterday and today,” World Journal of Surgery, vol. 34, no. 4, pp. 658–668, 2010.
- E. Erdal, C. Erdal, G. Bulut et al., “Mutation analysis of the Vangl2 coding region revealed no common cause for tetralogy of fallot,” Journal of International Medical Research, vol. 35, no. 6, pp. 867–872, 2007.
- C. Wansleeben, H. Feitsma, M. Montcouquiol, C. Kroon, E. Cuppen, and F. Meijlink, “Planar cell polarity defects and defective Vangl2 trafficking in mutants for the COPII gene Sec24b,” Development, vol. 137, no. 7, pp. 1067–1073, 2010.
- K. Sato and A. Nakano, “Mechanisms of COPII vesicle formation and protein sorting,” FEBS Letters, vol. 581, no. 11, pp. 2076–2082, 2007.
- A. Wessels and J. M. Pérez-Pomares, “The epicardium and epicardially derived cells (EPDCs) as cardiac stem cells,” Anatomical Record, Part A, vol. 276, no. 1, pp. 43–57, 2004.
- H. E. Olivey, L. A. Compton, and J. V. Barnett, “Coronary vessel development: the epicardium delivers,” Trends in Cardiovascular Medicine, vol. 14, no. 6, pp. 247–251, 2004.
- H. M. Phillips, V. Hildreth, J. D. Peat et al., “Non-cell-autonomous roles for the planar cell polarity gene vangl2 in development of the coronary circulation,” Circulation Research, vol. 102, no. 5, pp. 615–623, 2008.
- T. Goto, L. Davidson, M. Asashima, and R. Keller, “Planar cell polarity genes regulate polarized extracellular matrix deposition during frog gastrulation,” Current Biology, vol. 15, no. 8, pp. 787–793, 2005.
- J. B. Wallingford, “Vertebrate gastrulation: polarity genes control the matrix,” Current Biology, vol. 15, no. 11, pp. R414–R416, 2005.
- D. Y. Rhee, X. Q. Zhao, R. J. B. Francis, G. Y. Huang, J. D. Mably, and C. W. Lo, “Connexin 43 regulates epicardial cell polarity and migration in coronary vascular development,” Development, vol. 136, no. 18, pp. 3185–3193, 2009.
- D. L. Walker, S. J. Vacha, M. L. Kirby, and C. W. Lo, “Connexin43 deficiency causes dysregulation of coronary vasculogenesis,” Developmental Biology, vol. 284, no. 2, pp. 479–498, 2005.
- H. E. Olivey and E. C. Svensson, “Epicardial-myocardial signaling directing coronary vasculogenesis,” Circulation Research, vol. 106, no. 5, pp. 818–832, 2010.
- F. Feiguin, M. Hannus, M. Mlodzik, and S. Eaton, “The ankyrin repeat protein diego mediates frizzled-dependent planar polarization,” Developmental Cell, vol. 1, no. 1, pp. 93–101, 2001.
- K. Itoh, A. Jenny, M. Mlodzik, and S. Y. Sokol, “Centrosomal localization of Diversin and its relevance to Wnt signaling,” Journal of Cell Science, vol. 122, no. 20, pp. 3791–3798, 2009.
- T. Schwarz-Romond, C. Asbrand, J. Bakkers et al., “The ankyrin repeat protein diversin recruits casein kinase Iε to the β-catenin degradation complex and acts in both canonical Wnt and Wnt/JNK signaling,” Genes and Development, vol. 16, no. 16, pp. 2073–2084, 2002.
- H. Moeller, A. Jenny, H. J. Schaeffer et al., “Diversin regulates heart formation and gastrulation movements in development,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 43, pp. 15900–15905, 2006.
- D. Y. R. Stainier, “Zebrafish genetics and vertebrate heart formation,” Nature Reviews Genetics, vol. 2, no. 1, pp. 39–48, 2001.
- C. Thisse and L. I. Zon, “Organogenesis—heart and blood formation from the zebrafish point of view,” Science, vol. 295, no. 5554, pp. 457–462, 2002.
- A. Jenny, J. Reynolds-Kenneally, G. Das, M. Burnett, and M. Mlodzik, “Diego and Prickle regulate frizzled planar cell polarity signalling by competing for Dishevelled binding,” Nature Cell Biology, vol. 7, no. 7, pp. 691–697, 2005.
- C. Gao and Y.-G. Chen, “Dishevelled: the hub of Wnt signaling.,” Cellular Signalling, vol. 22, no. 5, pp. 717–727, 2010.
- S. L. Etheridge, S. Ray, S. Li et al., “Murine dishevelled 3 functions in redundant pathways with dishevelled 1 and 2 in normal cardiac outflow tract, cochlea, and neural tube development,” PLoS Genetics, vol. 4, no. 11, Article ID e1000259, 2008.
- C. C. Malbon and H.-Y. Wang, “Dishevelled: a mobile scaffold catalyzing development,” Current Topics in Developmental Biology, vol. 72, pp. 153–166, 2005.
- J. B. Wallingford and R. Habas, “The developmental biology of Dishevelled: an enigmatic protein governing cell fate and cell polarity,” Development, vol. 132, no. 20, pp. 4421–4436, 2005.
- J. de Calisto, C. Araya, L. Marchant, C. F. Riaz, and R. Mayor, “Essential role of non-canonical Wnt signalling in neural crest migration,” Development, vol. 132, no. 11, pp. 2587–2597, 2005.
- P. Pandur, D. Maurus, and M. Kühl, “Increasingly complex: new players enter the Wnt signaling network,” BioEssays, vol. 24, no. 10, pp. 881–884, 2002.
- L. M. Eisenberg and C. A. Eisenberg, “Wnt signal transduction and the formation of the myocardium,” Developmental Biology, vol. 293, no. 2, pp. 305–315, 2006.
- E. D. Cohen, Y. Tian, and E. E. Morrisey, “Wnt signaling: an essential regulator of cardiovascular differentiation, morphogenesis and progenitor self-renewal,” Development, vol. 135, no. 5, pp. 789–798, 2008.
- T. Brade, J. Männer, and M. Kühl, “The role of Wnt signalling in cardiac development and tissue remodelling in the mature heart,” Cardiovascular Research, vol. 72, no. 2, pp. 198–209, 2006.
- R. J. Garriock, S. L. D'Agostino, K. C. Pilcher, and P. A. Krieg, “Wnt11-R, a protein closely related to mammalian Wnt11, is required for heart morphogenesis in Xenopus,” Developmental Biology, vol. 279, no. 1, pp. 179–192, 2005.
- A. J. Mikels and R. Nusse, “Purified Wnt5a protein activates or inhibits beta-catenin-TCF signaling depending on receptor context.,” PLoS Biology, vol. 4, no. 4, article e115, 2006.
- M. A. Torres, J. A. Yang-Snyder, S. M. Purcell, A. A. DeMarais, L. L. McGrew, and R. T. Moon, “Activities of the Wnt-1 class of secreted signaling factors are antagonized by the Wnt-5A class and by a dominant negative cadherin in early Xenopus development,” Journal of Cell Biology, vol. 133, no. 5, pp. 1123–1137, 1996.
- V. C. Chen, R. Stull, D. Joo, X. Cheng, and G. Keller, “Notch signaling respecifies the hemangioblast to a cardiac fate,” Nature Biotechnology, vol. 26, no. 10, pp. 1169–1178, 2008.
- K. E. Schroeder, M. L. Condic, L. M. Eisenberg, and H. J. Yost, “Spatially regulated translation in embryos: asymmetric expression of maternal Wnt-11 along the dorsal-ventral axis in Xenopus,” Developmental Biology, vol. 214, no. 2, pp. 288–297, 1999.
- M. Ku and D. A. Melton, “Xwnt-11: a maternally expressed Xenopus wnt gene,” Development, vol. 119, no. 4, pp. 1161–1173, 1993.
- B. A. Afouda, J. Martin, F. Liu, A. Ciau-Uitz, R. Patient, and S. Hoppler, “GATA transcription factors integrate Wnt signalling during heart development,” Development, vol. 135, no. 19, pp. 3185–3190, 2008.
- A. Kispert, S. Vainio, L. Shen, D. H. Rowitch, and A. P. McMahon, “Proteoglycans are required for maintenance of Wnt-11 expression in the ureter tips,” Development, vol. 122, no. 11, pp. 3627–3637, 1996.
- H. Kirikoshi, H. Sekihara, and M. Katoh, “Molecular cloning and characterization of human WNT11,” International Journal of Molecular Medicine, vol. 8, no. 6, pp. 651–656, 2001.
- S. Ueno, G. Weidinger, T. Osugi et al., “Biphasic role for Wnt/β-catenin signaling in cardiac specification in zebrafish and embryonic stem cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 23, pp. 9685–9690, 2007.
- C. A. Eisenberg and L. M. Eisenberg, “WNT11 promotes cardiac tissue formation of early mesoderm,” Developmental Dynamics, vol. 216, no. 1, pp. 45–58, 1999.
- M. P. Flaherty, A. Abdel-Latif, Q. Li et al., “Noncanonical Wnt11 signaling is sufficient to induce cardiomyogenic differentiation in unfractionated bone marrow mononuclear cells,” Circulation, vol. 117, no. 17, pp. 2241–2252, 2008.
- M. Koyanagi, J. Haendeler, C. Badorff et al., “Non-canonical Wnt signaling enhances differentiation of human circulating progenitor cells to cardiomyogenic cells,” Journal of Biological Chemistry, vol. 280, no. 17, pp. 16838–16842, 2005.
- H. Terami, K. Hidaka, T. Katsumata, A. Iio, and T. Morisaki, “Wnt11 facilitates embryonic stem cell differentiation to Nkx2.5-positive cardiomyocytes,” Biochemical and Biophysical Research Communications, vol. 325, no. 3, pp. 968–975, 2004.
- I. I. Nagy, A. Railo, R. Rapila et al., “Wnt-11 signalling controls ventricular myocardium development by patterning N-cadherin and β-catenin expression,” Cardiovascular Research, vol. 85, no. 1, pp. 100–109, 2010.
- I. Shnitsar and A. Borchers, “PTK7 recruits dsh to regulate neural crest migration,” Development, vol. 135, no. 24, pp. 4015–4024, 2008.
- X. Lu, A. G. M. Borchers, C. Jolicoeur, H. Rayburn, J. C. Baker, and M. Tessier-Lavigne, “PTK7/CCK-4 is a novel regulator of planar cell polarity in vertebrates,” Nature, vol. 430, no. 6995, pp. 93–98, 2004.
- A. Paudyal, C. Damrau, V. L. Patterson et al., “The novel mouse mutant, chuzhoi, has disruption of Ptk7 protein and exhibits defects in neural tube, heart and lung development and abnormal planar cell polarity in the ear,” BMC Developmental Biology, vol. 10, article 87, 2010.
- T. Toyofuku, H. Zhang, A. Kumanogoh et al., “Dual roles of Sema6D in cardiac morphogenesis through region-specific association of its receptor, Plexin-A1, with off-track and vascular endothelial growth factor receptor type 2,” Genes and Development, vol. 18, no. 4, pp. 435–447, 2004.
- D. Bilder and N. Perrimon, “Localization of apical epithelial determinants by the basolateral PDZ protein Scribble,” Nature, vol. 403, no. 6770, pp. 676–680, 2000.
- D. Bilder, M. Li, and N. Perrimon, “Cooperative regulation of cell polarity and growth by Drosophila tumor suppressors,” Science, vol. 289, no. 5476, pp. 113–116, 2000.
- L. E. Dow, A. M. Brumby, R. Muratore et al., “hScrib is a functional homologue of the Drosophila tumour suppressor Scribble,” Oncogene, vol. 22, no. 58, pp. 9225–9230, 2003.
- Y. Qin, C. Capaldo, B. M. Gumbiner, and I. G. Macara, “The mammalian Scribble polarity protein regulates epithelial cell adhesion and migration through E-cadherin,” Journal of Cell Biology, vol. 171, no. 6, pp. 1061–1071, 2005.
- J. N. Murdoch, D. J. Henderson, K. Doudney et al., “Disruption of scribble (Scrb1) causes severe neural tube defects in the circletail mouse,” Human Molecular Genetics, vol. 12, no. 2, pp. 87–98, 2003.
- H. M. Phillips, H. J. Rhee, J. N. Murdoch et al., “Disruption of planar cell polarity signaling results in congenital heart defects and cardiomyopathy attributable to early cardiomyocyte disorganization,” Circulation Research, vol. 101, no. 2, pp. 137–145, 2007.
- L.-L. Ong, N. Kim, T. Mima, L. Cohen-Gould, and T. Mikawa, “Trabecular myocytes of the embryonic heart require N-cadherin for migratory unit identity,” Developmental Biology, vol. 193, no. 1, pp. 1–9, 1998.
- B. Bagatto, J. Francl, B. Liu, and Q. Liu, “Cadherin2 (N-cadherin) plays an essential role in zebrafish cardiovascular development,” BMC Developmental Biology, vol. 6, article 23, 2006.
- M. Montcouquiol, N. Sans, D. Huss et al., “Asymmetric localization of Vangl2 and Fz3 indicate novel mechanisms for planar cell polarity in mammals,” Journal of Neuroscience, vol. 26, no. 19, pp. 5265–5275, 2006.
- J. N. Murdoch, R. A. Rachel, S. Shah et al., “Circletail, a new mouse mutant with severe neural tube defects: chromosomal localization and interaction with the loop-tail mutation,” Genomics, vol. 78, no. 1-2, pp. 55–63, 2001.
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