Published online before print January 6, 2005, doi: 10.1161/01.RES.0000154912.08695.88
© 2005 American Heart Association, Inc.
Molecular Medicine |
Vangl2 Acts via RhoA Signaling to Regulate Polarized Cell Movements During Development of the Proximal Outflow Tract
From the Institute of Human Genetics (H.M.P., B.C., D.J.H.), University of Newcastle upon Tyne, UK; Medical Research Council Mammalian Genetics Unit (J.N.M.), Harwell, UK; and the Neural Development Unit (A.J.C.), Institute of Child Health, University College London, UK.
Correspondence to Dr Deborah Henderson, Institute of Human Genetics, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK. E-mail D.J.Henderson{at}ncl.ac.uk
Loop-tail (Lp) mice develop double outlet right ventricle and aortic arch defects, and the defects are caused by mutations in the Vangl2 gene. Vangl2 mRNA is found in the outflow tract myocardium, including the myocardializing cells that migrate into the outflow tract cushions. Analysis of muscularization of the outflow tract septum showed that this process is compromised in Lp/Lp fetuses. Vangl2 is a component of the noncanonical Wnt, planar cell polarity (PCP) pathway that signals via RhoA. We therefore looked for evidence of polarization in myocardializing cells. In wild-type fetuses, myocardializing cells extend lamellipodia and filopodia into the cushion tissue and reorganize their actin cytoskeleton from a cortical form to stress fibers; behaviors that are characteristic of polarized cells. In contrast, Lp/Lp littermates do not extend lamellipodia or filopodia into the cushion tissue, and their actin remains in a cortical form, suggesting that polarized cell migration of myocardializing cells is inhibited in Lp/Lp. Several other components of the PCP pathway are also localized in the outflow tract myocardium. In wild-type fetuses, the myocardializing cells coexpress RhoA and one of its downstream mediators, ROCK1. RhoA expression is disrupted in Lp/Lp, and is lost from the myocardial-cushion tissue interface, including the presumptive myocardializing cells. These data suggest that Vangl2 is required for the polarization and movement of myocardializing cells into the outflow tract cushions, and that RhoA and ROCK1 are downstream mediators of the PCP signaling pathway in the developing outflow tract.
Key Words: congenital heart defects • genes • mouse mutant • development • cardiac muscle
Related Article:
Circ. Res. 2005 96: 274-276.
This article has been cited by other articles:
 |
|
 |
|
  J. M. Perez-Pomares Myocardial-Coronary Interactions: Against the Canon Circ. Res., March 14, 2008; 102(5): 513 - 515. [Full Text] [PDF]
|
|
|
|
|
|
H. M. Phillips, V. Hildreth, J. D. Peat, J. N. Murdoch, K. Kobayashi, B. Chaudhry, and D. J. Henderson Non-Cell-Autonomous Roles for the Planar Cell Polarity Gene Vangl2 in Development of the Coronary Circulation Circ. Res., March 14, 2008; 102(5): 615 - 623. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Torban, A.-M. Patenaude, S. Leclerc, S. Rakowiecki, S. Gauthier, G. Andelfinger, D. J. Epstein, and P. Gros Genetic interaction between members of the Vangl family causes neural tube defects in mice PNAS, March 4, 2008; 105(9): 3449 - 3454. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. D. Cohen, Y. Tian, and E. E. Morrisey Wnt signaling: an essential regulator of cardiovascular differentiation, morphogenesis and progenitor self-renewal Development, March 1, 2008; 135(5): 789 - 798. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Rohr, C. Otten, and S. Abdelilah-Seyfried Asymmetric Involution of the Myocardial Field Drives Heart Tube Formation in Zebrafish Circ. Res., February 1, 2008; 102(2): e12 - e19. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Conti and R. S. Adelstein Nonmuscle myosin II moves in new directions J. Cell Sci., January 1, 2008; 121(1): 11 - 18. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Bastock and D. Strutt The planar polarity pathway promotes coordinated cell migration during Drosophila oogenesis Development, September 1, 2007; 134(17): 3055 - 3064. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. S. Hakim, L. A. DiMichele, J. T. Doherty, J. W. Homeister, H. E. Beggs, L. F. Reichardt, R. J. Schwartz, J. Brackhan, O. Smithies, C. P. Mack, et al. Conditional Deletion of Focal Adhesion Kinase Leads to Defects in Ventricular Septation and Outflow Tract Alignment Mol. Cell. Biol., August 1, 2007; 27(15): 5352 - 5364. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. E. Davis and N. Katsanis Cell Polarization Defects in Early Heart Development Circ. Res., July 20, 2007; 101(2): 122 - 124. [Full Text] [PDF]
|
|
|
|
|
|
H. M. Phillips, H. J. Rhee, J. N. Murdoch, V. Hildreth, J. D. Peat, R. H. Anderson, A. J. Copp, B. Chaudhry, and D. J. Henderson Disruption of Planar Cell Polarity Signaling Results in Congenital Heart Defects and Cardiomyopathy Attributable to Early Cardiomyocyte Disorganization Circ. Res., July 20, 2007; 101(2): 137 - 145. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Abstracts Heart, June 1, 2007; 93(suppl_1): A5 - A105. [Full Text] [PDF]
|
|
|
|
|
|
D. Ai, X. Fu, J. Wang, M.-F. Lu, L. Chen, A. Baldini, W. H. Klein, and J. F. Martin Canonical Wnt signaling functions in second heart field to promote right ventricular growth PNAS, May 29, 2007; 104(22): 9319 - 9324. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Brade, J. Manner, and M. Kuhl The role of Wnt signalling in cardiac development and tissue remodelling in the mature heart Cardiovasc Res, November 1, 2006; 72(2): 198 - 209. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Brown, D. P. Del Re, and M. A. Sussman The Rac and Rho Hall of Fame: A Decade of Hypertrophic Signaling Hits Circ. Res., March 31, 2006; 98(6): 730 - 742. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. B. Wallingford and R. Habas The developmental biology of Dishevelled: an enigmatic protein governing cell fate and cell polarity Development, October 15, 2005; 132(20): 4421 - 4436. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J.B. van den Hoff and A. F.M. Moorman Wnt, a Driver of Myocardialization? Circ. Res., February 18, 2005; 96(3): 274 - 276. [Full Text] [PDF]
|
|