Published online before print June 7, 2007, doi: 10.1161/CIRCRESAHA.106.142406
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© 2007 American Heart Association, Inc.
Molecular Medicine |
Disruption of Planar Cell Polarity Signaling Results in Congenital Heart Defects and Cardiomyopathy Attributable to Early Cardiomyocyte Disorganization
From the Institute of Human Genetics (H.M.P., H.J.R., V.H., J.D.P., B.C., D.J.H.), Newcastle University, Newcastle upon Tyne; Medical Research Council Mammalian Genetics Unit (J.N.M.), Harwell, Oxon; and Cardiac Unit (R.H.A.) and Neural Development Unit (A.J.C.), Institute of Child Health, University College London, UK.
Correspondence to Dr Deborah J. Henderson, Newcastle University, Institute of Human Genetics, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, United Kingdom. E-mail d.j.henderson{at}ncl.ac.uk
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Abstract |
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The Drosophila scribble gene regulates apical-basal polarity and is implicated in control of cellular architecture and cell growth control. Mutations in mammalian Scrib (circletail; Crc mutant) also result in abnormalities suggestive of roles in planar cell polarity regulation. We show that Crc mutants develop heart malformations and cardiomyopathy attributable to abnormalities in cardiomyocyte organization within the early heart tube. N-Cadherin is lost from the cardiomyocyte cell membrane and cell–cell adhesion is disrupted. This results in abnormalities in heart looping and formation of both the trabeculae and compact myocardium, which ultimately results in cardiac misalignment defects and ventricular noncompaction. Thus, these late abnormalities arise from defects occurring at the earliest stages of heart development. Mislocalization of Vangl2 in Crc/Crc cardiomyocytes suggests Scrib is acting in the planar cell polarity pathway in this tissue. Moreover, 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. We propose that heterozygosity for mutations in different genes in the planar cell polarity pathway may be an important mechanism for congenital heart defects and cardiomyopathy in humans.
Key Words: cardiac development • cardiomyopathy • congenital heart defects • planar cell polarity • Scrib
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Introduction |
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Although cardiovascular defects are the commonest congenital malformations, our understanding of their pathogenesis remains rudimentary. The genetic element to the etiology of these defects is suggested by the heritability of individual heart malformations. Intriguingly, there is an increased incidence of a variety of cardiac abnormalities in relatives of those with structural heart defects.1 Although we know many of the key genes required for heart development, homozygous mutations of a single gene cannot explain the occurrence of a single disorder within the patient population. Similarly, there is considerable variability in phenotype following homozygosity for mutation of a single gene.1
Scrib is orthologous to the Drosophila scribble gene that controls apical–basal polarity and tissue growth.2,3 Although human hScrib can compensate for its Drosophila counterpart,4 suggesting conservation of essential functional domains, its role in higher species may have altered as mammalian Scrib plays essential roles in cell–cell adhesion.5 Mutations in mouse Scrib6 (circletail mutant; Crc) result in neural tube defects, shortened body axis, and abnormalities in hair cell orientation in the inner ear, similar to those observed when the planar cell polarity (PCP) gene Vangl2 is disrupted in the loop-tail (Lp) mutant.7,8 Lp and Crc mice genetically interact,7 with a proportion of embryos that are heterozygous for mutations in both genes displaying neural tube defects characteristic of homozygous mutations of either gene alone. This, together with similar phenotypes observed in other PCP pathway mutants,9,10 suggests that both Scrib and Vangl2 are required for PCP signaling during early embryogenesis. We have previously described abnormal cardiomyocyte polarity and cardiac defects in the Lp mutant.11,12 The similarities between Lp and Crc prompted us to investigate whether Scrib is also essential for heart development. Importantly, we asked whether heterozygosity for mutations in multiple genes of the PCP pathway can cause isolated cardiac defects.
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Materials and Methods |
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Embryo Preparation and Analysis
Crc and Lp mice were bred and genotyped as described previously.6,7 No heart malformations were observed in Lp/+ or Crc/+ embryos (>100 studied), and these were used with +/+ embryos as controls. CD1 mice were obtained from Charles River (UK). All animals were maintained as required by the UK Animals (Scientific Procedures) Act 1986.
Histology and Immunohistochemistry
Hematoxylin and eosin staining was performed using standard protocols. Immunohistochemistry11 was performed using antibodies against the following: Vangl213; myosin (clone NOQ7.5.4D), 
-actinin, and laminin (Sigma); and N-cadherin (BD Transduction Laboratories). ZO-1 was obtained from the Developmental Studies Hybridoma Bank (University of Iowa), and anti-Scrib antibody from P. Humbert (Peter Macullum Cancer Institute, Melbourne, Australia). Antibodies were visualized using laser-scanning confocal microscopy or immunoperoxidase staining with diaminobenzidine, using appropriate controls.
cDNA Probes and In Situ Hybridization
Whole-mount and slide in situ hybridization6,7 was performed using cDNA probes for Scrib,6 Tbx5 (D Brook, Nottingham University, UK), Tbx20 (J. Sowden, University of London, UK), Mlc2a, Mlc2v (D. Srivastava, University of California, San Francisco), and Nppa (A. Moorman, University of Amsterdam, The Netherlands).
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Results |
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Scrib Is Essential for Cardiomyocyte Organization in the Primary Heart Tube
Until late in gestation, mouse cardiomyocytes present a rounded, nonpolarized morphology, and many components of intercellular junctions are distributed throughout their cell membrane.14 Scrib mRNA and protein are first expressed in the primitive heart tube at embryonic day (E)8.5, with the protein localizing to the cell membrane but showing no evidence of polarized expression (Figure 1A and 1B). Although Scrib protein is absent from Crc/Crc embryos (data not shown), their cardiomyocytes migrate and coalesce to form a fused primary heart tube (Figure 1C and 1D). Closer examination of these early hearts reveals marked abnormalities when compared with wild-type controls; the cardiomyocytes are of variable size and shape and the myocardial wall also varies in thickness (Figure 1E through 1H).
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The integrity of the heart tube is dependent on N-cadherin,15,16 which is tightly localized to the lateral membranes of cardiomyocytes from the earliest point of heart tube formation (Figure 1E). In Crc/Crc embryos, N-cadherin is displaced from the cardiomyocyte membranes and is found in the cytoplasmic compartment at E8.5 and E9.5 (Figure 1F and data not shown). Similarly, ß-catenin, which normally localizes with N-cadherin to the adherens junction, is also displaced (data not shown). Thus, Scrib is required for the correct localization of N-cadherin and ß-catenin at the lateral cell membrane in the primitive myocardium. Furthermore, although the tight junction marker ZO-1 is maintained at the lateral cell membrane of Crc/Crc cardiomyocytes, it presents a double, rather than the normal single, band of labeling between many of the cells (Figure 1G and 1H), suggesting the cells are not juxtaposed. This finding is in keeping with the role of Scrib as a regulator of cell adhesion,7 although Scrib has not been previously shown to perform this role in mesodermal derivatives.
Cardiac Looping and Chamber Expansion Are Disrupted in Crc
As looping progresses, there is expansion of different regions of the primitive heart tube to give rise to the atria and the ventricles. Cells from the second heart field also add to the atria, right ventricle, and outflow tract during this period of ballooning17 but do not make a major contribution to the left ventricle. Analysis of chamber-specific markers in Crc/Crc embryos (including Mlc2a, Mlc2v, Tbx5, Tbx20, and Nppa) demonstrates that atria and ventricular specification is normal (Figure 2 and data not shown). Analysis of both second heart field markers (Islet1, Tbx20) and outflow tract length in Crc/Crc embryos supports normal addition of second heart field cells to the forming heart (data not shown). However, loss of Scrib prevents normal heart looping. Although initial rightward direction of looping occurs normally in all Crc/Crc embryos, looping itself is incomplete such that the shape of the heart was clearly abnormal in the Crc/Crc embryos at E9.5 (Figure 2A and 2B). These abnormalities are maintained at E10.5 and can still be seen in the heart at late stages of gestation (Figure 2C through 2H).
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Scrib mRNA is expressed throughout the entire prospective chamber myocardium in the normal heart tube at E8.5 (Figure 1A). However, as the ventricles begin to develop compact and trabeculated portions (E10.5), Scrib transcripts are more abundant in the compact myocardium than in the trabeculated myocardium. Message levels remain high in the compact layer of the ventricular myocardium at E12.5 (Figure 3B) until at least E15.5 (the latest stage examined; data not shown). Analysis of Scrib protein expression confirmed and extended these findings, demonstrating that Scrib continues to be associated with the cell membrane between E12.5 and E16.5 (Figure 3C and data not shown), with the highest levels on the basolateral surface of the subepicardial cardiomyocytes. In the adult myocardium, Scrib localizes to the lateral membranes of cardiomyocytes (Figure 3D). These data suggest that Scrib may be playing roles in the chamber myocardium during the period of rapid chamber expansion and in the adult.
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Detailed analyses, using a broad range of morphological criteria, confirmed that the abnormalities in the shape and size of the ventricles were not caused by developmental delay but reflect a specific defect in ventricular growth. As Fgf2 is known to be a major mitogenic factor required for myocardial proliferation and growth,18 we investigated whether the levels or localization of Fgf2 and its receptors might be abnormal in Crc/Crc embryos during the period of rapid myocardial growth. However, no differences in either the level or localization of Fgf2, FGFR1, or FGFR2 can be observed in Crc/Crc embryos when compared with their control littermates (Figure 3E through 3H and data not shown).
Abnormalities in Development of the Arterial Wall in Crc
Scrib mRNA and protein is normally found in the developing outflow tract myocardium at E8.5 to E10.5 but is absent from the aortic sac and the forming pharyngeal arch arteries (Figure 3I and 3J). From E11.5 onward, and in the adult, Scrib is found in the walls of the great arteries, where it localizes to the tunica media (Figure 3K and 3L). The arch arteries appear to form normally in Crc/Crc embryos (data not shown), but by E12.5, the vessels are tortuous (Figure 3M and 3N). Abnormal arch artery remodeling is found in a high proportion of Crc/Crc fetuses later in gestation (Table I in the online data supplement, available at http://circres.ahajournals.org). This suggests that stabilization of the pharyngeal arch arteries is abnormal in Crc/Crc; this is further supported by abnormal localization and intensity of staining for -smooth muscle actin within the pharyngeal arterial walls (Figure 3M through 3P).
Early Abnormalities in Myocardial Organization Result in Cardiomyopathy
By E10.5, the ventricles in Crc/Crc mutants are already markedly smaller and the trabeculae less well formed when compared with developmentally matched control embryos (Figure 4A and 4B). This is more striking at E13.5, with the trabeculae frequently appearing clubbed and resembling those of much younger embryos (Figure 4C through 4H). In addition, the ventricular wall is thinned and the cardiomyocytes are less compacted. By E16.5, the normal ventricle has a thick compact layer. In contrast, Crc/Crc ventricles remain markedly hypoplastic with little compact layer, and although the ventricular wall has thickened compared with Crc/Crc embryos at E13.5, prominent trabeculae with deep intratrabecular recesses extending to the subepicardial region are still apparent in some regions (Figure 4I through 4L). Hypertrophy of the ventricular septum is also a common finding. Importantly, the epicardium appears to be normally applied in Crc/Crc embryos from E10.5 onwards (Figure 4E and 4F and data not shown). These abnormalities in the organization of the ventricular myocardium are similar to those seen in the human cardiomyopathy, ventricular noncompaction.19
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We have observed abnormalities in the muscularization of the outflow tract cushions in the Lp mutant,12 which appear to be related to abnormalities in cardiomyocyte polarity. We therefore undertook to determine whether similar defects were present in Crc/Crc fetuses. Analysis at E12.5 reveals a marked reduction in the numbers and orientation of cardiomyocytes extending into the outflow tract cushions in Crc/Crc hearts (Figure 4M and 4N). These defects can still be seen at E13.5 (Figure 4O and 4P), and failure to form a muscular outlet septum is a common finding later in gestation (supplemental Table I). These data suggest that there is an abnormality in the polarization and migration of myocardializing cardiomyocytes in the outflow tract.
A Spectrum of Congenital Heart Defects in Crc
Examination of litters at E16.5 to E17.5 revealed that although body size is similar between Crc/Crc embryos and littermates, the ventricular chambers of Crc/Crc hearts are smaller and abnormally shaped (Figure 5A through 5F). Cardiovascular defects, most commonly affecting the ventriculoarterial junctions, the aortic arch arteries and the ventricular myocardium, were seen in all Crc/Crc fetuses examined between E13.5 to E17.5 (supplemental Table I). One third (6/21) had parallel arterial trunks (compare Figure 5C and 5H with 5D and 5P) associated with transposition of the great arteries (discordant ventriculo-arterial connections) or double-outlet right ventricle. Atrioventricular septal defects were also seen in many fetuses (Figure 4D). Additionally, abnormal asymmetrical remodeling of the aortic arch arteries was found in half of Crc/Crc fetuses sectioned between E13.5 to E16.5 (supplemental Table I).
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Examination of a number of markers of junctional complexes, cell membrane and sarcomeric constituents in Crc/Crc hearts at E16.5 reveals that the ultrastructure of the myocardium has normalized by this stage of development (Figure 6), although areas of disorganization are still apparent. Moreover, laminin staining of the extracellular matrix between the cardiomyocytes is patchy and reveals enlarged spaces between the cardiomyocytes in Crc/Crc fetuses (Figure 6A and 6B).
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Double Heterozygous Mutations in Scrib and Vangl2 Cause Cardiac Abnormalities As a Primary Defect
Previous studies have demonstrated a genetic interaction between Lp and Crc producing defects in the formation of the neural tube and the cochlea.6–8 Scrib and Vangl2 are both expressed in the developing ventricles and outflow tract (Figure 7A and 7B and Figure 3), and because they are capable of physical interaction20 and play related roles in development, we investigated whether the 2 proteins colocalize in cardiomyocytes and whether their localization is codependent. Vangl2 mRNA is first detected in the heart of the wild-type embryos at E9.5.12 Like Scrib, Vangl2 protein localizes to the cell membrane surrounding the cardiomyocytes although the pattern is more punctuate (Figure 7A through 7D). Neither Vangl2 nor Scrib shows polarized expression in cardiomyocytes. Scrib protein localizes normally to the cell membrane in Lp/Lp cardiomyocytes (Figure 7E). In contrast, the distribution of Vangl2 protein is disrupted in Crc/Crc embryos at E9.5; although the cardiomyocytes are irregular in shape and size, it is clear that more Vangl2 localizes within the cytoplasmic compartment and less with the cell membrane than in control embryos (Figure 7F). This suggests that 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.
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To determine whether this interaction is important for the development of the cardiovascular system, we examined the heart and aortic arch arteries in ten Lp/+,Crc/+ double heterozygotes (supplemental Table I) between stages E13.5 and E17.5. Six of the 10 fetuses exhibited the severe neural tube defect craniorachischisis, whereas the remaining 4 did not, excluding this as a primary cause of the cardiovascular defects in these mutants. Nine of 10 of the Lp/+,Crc/+ fetuses manifested cardiovascular abnormalities, the majority of which closely resembled those seen in Crc homozygotes (Figure 8A through 8C). Overriding aorta, parallel trunks, and retention of the right fourth arch artery were discovered in a Lp/+,Crc/+ fetus that did not manifest either craniorachischisis or gastroschisis. Evidence of ventricular noncompaction was also observed in Lp/Crc double heterozygotes (Figure 8D and supplemental Table I). Importantly, these studies demonstrate that heterozygosity for mutations in 2 different genes involved in PCP can lead to isolated abnormalities in cardiac development (ie, in the absence of major defects in other organ systems).
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Discussion |
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This study indicates that it is possible for subtle abnormalities in the cellular organization of the primitive heart tube to manifest as gross abnormalities of chamber formation and connections of the great vessels in the latter stages of development. We show that Scrib is required for normal cardiac looping and that its absence produces clinically relevant congenital heart defects in the mouse model. In addition, we show that Scrib function is required for normal Vangl2 localization in the developing myocardium and that combined haploinsufficiency for these genes is sufficient to produce the full spectrum of congenital heart defects seen with homozygosity for either Scrib or Vangl2 mutations alone. Importantly, the malformations of the cardiovascular system observed at the end of gestation do not obviously suggest that there has been an abnormality at the earliest stages of heart development.
The Drosophila scribble gene regulates apical–basal polarity and functions as a tumor suppressor, regulating cell growth; scribble mutants exhibit disrupted cellular architecture.3,4 Although in zebrafish, mutations in genes known to be crucial to the generation of apical–basal polarity have been shown to be important for fusion of the linear heart tube and myocardial coherence,21 Crc/Crc embryos achieve a fused heart tube. Greater similarities are found between Crc and the N-cadherin zebrafish mutant, "glass onion," which develops a disorganized myocardium with abnormally shaped and loosely-aggregated cardiomyocytes.22 Qin et al5 have shown Scrib depletion disrupts E-cadherin–mediated cell–cell adhesion in cultured kidney epithelial cells, supporting a key role in cell–cell adhesion. Other studies, however, have been less clear about the role of Scrib in cell–cell adhesion.23 Whatever the specific role for Scrib in this process, our data suggest that loss of Scrib function disrupts cardiomyocyte organization. The cells are loosely aggregated and lose membrane expression of N-cadherin. Studies in chicken embryos have shown that N-cadherin is also essential for trabecular formation,16 suggesting that loss of N-cadherin from the cardiomyocyte membrane in Crc/Crc embryos may be responsible for the abnormalities in formation of the trabeculae and the compact myocardium. Although the functional significance of the localization of Scrib protein to the basolateral domain of subepicardial cardiomyocytes remains unclear, it is tempting to speculate that this relates to the interactions between the myocardium and epicardium required for myocardial cell growth and compaction (18 and references therein). The epicardium is known to release factors required for growth and maturation of the ventricular wall and although an intact epicardium forms in Crc/Crc embryos, loss of Scrib in the subepicardial myocardium might prevent normal myocardial response to epicardial trophic factors. For example, Fgf2 signaling is known to be central to the growth and proliferation of the ventricular wall and requires an intact epicardium for its normal expression.18 Because levels and localization of Fgf2 and its receptors were normal in Crc/Crc hearts, other signaling pathways that might require Scrib function in the myocardium will be a focus of future studies.
We have shown that loss of Scrib in the early heart tube does not prevent the formation of an intact heart tube, but does affect the organization of the cardiomyocytes within it. This has important and far ranging implications for cardiac form. Although the precise mechanism underlying cardiac looping remains elusive, it has been suggested that a developing cytoskeletal network results in changes in cell shape that cause the heart to initiate looping.24,25 Abnormalities in the shape of individual cardiomyocytes, and the cytoarchitecture of the developing myocardium as a whole, as in Crc, might disrupt the shape of the looping heart. Many studies have shown associations between early abnormalities in the shape of the heart loop and subsequent defects in cardiac septation and alignment. Indeed, it has been suggested that even subtle abnormalities in looping can result in defects in the outflow region of the heart.26 Thus, abnormalities in the shape and organization of the cardiomyocytes in the linear heart tube of Crc/Crc may be the fundamental cause of the defects in heart looping, septation, and alignment seen in later gestation. In addition to defects in the organization of ventricular cardiomyocytes, abnormal myocardialization of the outflow tract cushions is seen in Crc/Crc fetuses, as in Lp.12 These myocardializing cells are the most obviously polarized, migrating cardiomyocytes in the heart at these stages of development and clearly support a role for Scrib in cell polarity and migration, as shown in astrocytes and cultured epithelial cells.27,28 However, because abnormalities in outflow tract alignment were seen in Crc/Crc before initiation of myocardialization at E11.5, it is likely that the outflow alignment defects arise from the initial disruption of cardiac looping, which itself results from disorganization of the cardiomyocytes within the primitive heart tube, rather than from defects in formation of the muscular outlet septum. In contrast, our studies suggest that abnormalities in aortic arch artery patterning do not occur because of a early failure of formation but rather because of abnormal remodeling, perhaps because they are not stabilized by smooth muscle cells. Alternatively, the arch artery remodeling defects may be secondary to hemodynamic consequences of the intracardiac defects. Whatever the cause, continuing high-level expression of Scrib protein in the smooth muscle layers of adult great arteries and in the ventricular myocardium suggests continuing roles for Scrib in these tissues. Scrib therefore appears to plays roles at the earliest stages of cardiac development and in the adult.
Although Scrib is implicated in the regulation of apical–basal polarity in Drosophila, there is little evidence for such a role in mammals and a role in PCP seems more likely as Crc mutants demonstrate abnormal PCP specification, best illustrated by abnormal orientation of stereocilia in the organ of Corti.8 Together with the genetic interaction between Crc and Lp,7 these data suggest that Scrib may be required for establishment of PCP in vertebrates. The temporal relationship between Scrib and Vangl2, the finding that Scrib protein expression is undisturbed in Lp/Lp cardiomyocytes, and the observation that Vangl2 protein is lost from the cell membrane in Crc/Crc mutants strongly suggest that Scrib is required for correct localization of Vangl2. Furthermore, the finding of a Lp/+,Crc/+ double heterozygote with abnormalities of the outflow tracts and aortic arches, in the absence of either craniorachischisis or gastroschisis, proves that these cardiovascular defects are not secondary to these other developmental defects and also shows how disruption of PCP signaling can produce isolated cardiovascular defects.
Multiple heterozygosity for gene mutations has been suggested as a cause of cardiovascular defects.1 Our observation that heterozygosity for mutations in Scrib and Vangl2 leads to cardiac defects supports this and implies that mutations of genes in this PCP pathway might explain some forms of human congenital heart defects. This work suggests that defects at the earliest stages of heart development can result in defects of relevance in the clinic and that mutation screening in congenital heart disease should focus not only on a new panel of genes within PCP signaling but also on the heterozygosity for mutations in different genes.
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Acknowledgments |
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Sources of Funding
This research was funded by the British Heart Foundation (grants BS/05/003, PG/02/035/13593, and PG/05/041), the Medical Research Council (G9901317), and the Wellcome Trust (068883).
Disclosures
None.
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Footnotes |
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Original received October 11, 2006; revision received May 2, 2007; accepted May 25, 2007.
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