Disruption of Planar Cell Polarity Signaling Results in Congenital Heart Defects and Cardiomyopathy Attributable to Early Cardiomyocyte Disorganization

Abstract

Abstract-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. (Circ Res. 2007;101:137-145.)

Cilia and coordination of signaling networks during heart development

“…2,189 Mutations in Vangl2 disrupt migration of cells into the OFT and this is associated with impaired OFT myocardialization as well as ventricular and OFT septal defects. 189 The localization of Vangl2 during heart development is dependent on Scribble, another PCP component, 204 and in agreement with this, Scribble phenotypes are reminiscent of Vangl2 mutants. 204,205 In support of the idea that noncanonical Wnt signaling is associated with cardiac primary cilia, Gmap210 −/− mouse embryos with impaired ciliogenesis due to impaired ciliary targeting have cardiac phenotypes resembling those observed in multiple PCP mutants, including Vangl2, Dvl2, and Scribble mutant mice.…”

“…189 The localization of Vangl2 during heart development is dependent on Scribble, another PCP component, 204 and in agreement with this, Scribble phenotypes are reminiscent of Vangl2 mutants. 204,205 In support of the idea that noncanonical Wnt signaling is associated with cardiac primary cilia, Gmap210 −/− mouse embryos with impaired ciliogenesis due to impaired ciliary targeting have cardiac phenotypes resembling those observed in multiple PCP mutants, including Vangl2, Dvl2, and Scribble mutant mice. 147 Although kidney-specific depletion of Ift20 in mice resulted in defective Wnt signaling in the affected tissues, 206 it remains to be determined whether the cardiac phenotypes observed in the Gmap210 -/-mouse are directly associated with defective non-canonical Wnt signaling.…”

Canonical Wnt signaling functions in second heart field to promote right ventricular growth

“…The gene mutated in Lp is Vangl2, a homolog of the Drosophila planar cell polarity gene Strabismus. Recent work has shown that Vangl2 functions in the OFT myocardium to regulate OFT septation (40).…”

Probing chromatin landscape reveals roles of endocardial TBX20 in septation

“…Subsequently, cardiomyocytes that flank cushion mesenchyme protrude into cushion mesenchyme. This process, called myocardialization, involves polarized cell movements of OFT cardiomyocytes (18,19). In control embryos at E13.5, sarcomeric α-actinin-expressing (Actn2-expressing) cardiomyocytes invaded the OFT septum, and cells protruding from the left and right sides met at the base of the proximal OFT septum ( Figure 3B).…”

“…We found that loss of TBX20 in endocardial lineages resulted in decreased myocardialization of the OFT, indicating a disturbed crosstalk between endocardial lineages and cardiomyocytes. Myocardialization involves polarized cell movements of OFT cardiomyocytes and is required for normal OFT alignment and septation (18,19). Decreased myocardialization in Tie2-Cre Tbx20 fl/null mutants probably contributes to the observed DORV phenotype.…”