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Molecular and Cellular Biology, August 2007, p. 5352-5364, Vol. 27, No. 15
0270-7306/07/$08.00+0     doi:10.1128/MCB.00068-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Conditional Deletion of Focal Adhesion Kinase Leads to Defects in Ventricular Septation and Outflow Tract Alignment{triangledown} ,{dagger}

Zeenat S. Hakim,1 Laura A. DiMichele,1 Jason T. Doherty,1 Jonathon W. Homeister,1,2 Hilary E. Beggs,3,4 Louis F. Reichardt,4,5 Robert J. Schwartz,6 Joseph Brackhan,1 Oliver Smithies,1 Christopher P. Mack,1,2 and Joan M. Taylor1,2*

Department of Pathology,1 Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, North Carolina 27599,2 Department of Opthamology,3 Department of Physiology,4 Howard Hughes Medical Institute, University of California, San Francisco, California 94143,5 Institute of Biosciences and Technology, Houston, Texas 770306

Received 12 January 2007/ Returned for modification 20 February 2007/ Accepted 17 May 2007

To examine a role for focal adhesion kinase (FAK) in cardiac morphogenesis, we generated a line of mice with a conditional deletion of FAK in nkx2-5-expressing cells (herein termed FAKnk mice). FAKnk mice died shortly after birth, likely resulting from a profound subaortic ventricular septal defect and associated malalignment of the outflow tract. Additional less penetrant phenotypes included persistent truncus arteriosus and thickened valve leaflets. Thus, conditional inactivation of FAK in nkx2-5-expressing cells leads to the most common congenital heart defect that is also a subset of abnormalities associated with tetralogy of Fallot and the DiGeorge syndrome. No significant differences in proliferation or apoptosis between control and FAKnk hearts were observed. However, decreased myocardialization was observed for the conal ridges of the proximal outflow tract in FAKnk hearts. Interestingly, chemotaxis was significantly attenuated in isolated FAK-null cardiomyocytes in comparison to genetic controls, and these effects were concomitant with reduced tyrosine phosphorylation of Crk-associated substrate (CAS). Thus, it is possible that ventricular septation and appropriate outflow tract alignment is dependent, at least in part, upon FAK-dependent CAS activation and subsequent induction of polarized myocyte movement into the conal ridges. Future studies will be necessary to determine the precise contributions of the additional nkx2-5-derived lineages to the phenotypes observed.

* Corresponding author. Mailing address: Department of Pathology and Lab Medicine, 501 Brinkhous-Bullitt Bldg. CB 7525, University of North Carolina, Chapel Hill, NC 27599. Phone: (919) 843-5512. Fax: (919) 966-6718. E-mail: jmt3x{at}med.unc.edu

{triangledown} Published ahead of print on 25 May 2007.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, August 2007, p. 5352-5364, Vol. 27, No. 15
0270-7306/07/$08.00+0     doi:10.1128/MCB.00068-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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