Disruption of planar cell polarity signaling results in congenital heart defects and cardiomyopathy attributable to early cardiomyocyte disorganization.
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.
Phillips
Helen M
HM
Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, United Kingdom.
Rhee
Hong Jun
HJ
Murdoch
Jennifer N
JN
Hildreth
Victoria
V
Peat
Jonathan D
JD
Anderson
Robert H
RH
Copp
Andrew J
AJ
Chaudhry
Bill
B
Henderson
Deborah J
DJ
D000818:Animals; D001947:Breeding; D009202:Cardiomyopathies / Q000151:congenital / Q000378:metabolism* / Q000473:pathology; D016764:Cell Polarity / Q000235:genetics*; D006330:Heart Defects, Congenital / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006352:Heart Ventricles / Q000196:embryology / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D021381:Protein Transport / Q000235:genetics
D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; C431577:Ltap protein, mouse; C508433:scrib protein, mouse