Abstract 3410: FAK is Required for Neural Crest Cell Remodeling of the Cardiac Outflow Tract

Abstract

Background: Cardiac neural crest cells (NCCs) participate in the remodeling of the outflow tract and pharyngeal arch arteries during cardiovascular development. Abnormal growth factor and integrin signaling in cardiac NCCs leads to cardiovascular malformations. Focal adhesion kinase (FAK) is a ubiquitous protein kinase that transduces integrin and growth factor signaling pathways. However, a direct role for FAK in cardiac NCC morphogenesis has not been demonstrated. Here we have used a Cre/loxP method for NCC-specific deletion of FAK in mouse embryos. Results: We found that targeted deletion of FAK in NCC results in craniofacial and cardiovascular malformations, leading to early postnatal lethality. Mutant mice display cleft palate together with several cardiovascular defects, including persistent truncus arteriosus, transposition of the great arteries, overriding aorta, ventricular septal defect and type B interruption of the aortic arch, all of which resemble common forms of human congenital heart disease. We found that NCC counts in the outflow tract of FAK mutant and control littermates are similar at E11, suggesting that FAK is not required for cardiac NCC migration to the outflow tract. Furthermore, NCCs appear to differentiate normally into smooth muscle cells in the outflow tract of FAK conditional mutant embryos at E11 and E12.5. In contrast, NCCs in the aortic arch arteries of FAK conditional mutants show impaired differentiation into smooth muscle cells in these embryonic stages. Additionally, we observed that rotation of the outflow tract fails to occur by E11 in FAK mutants, resulting in a dextroposed aortic root. Moreover, FAK-deficient NCCs form a less compact mesenchyme in the conotruncal cushions and show disorganized F-actin stress fibers in the aorticopulmonary septum. Conclusions: Our results indicate that FAK plays an essential role in the development of the cardiac outflow tract and in the remodeling of aortic arch arteries. However, it is dispensable for migration and differentiation of cardiac NCC in the outflow tract. Further studies with this novel model of congenital heart disease may help elucidate the NCC signaling pathways that orchestrate septation of the outflow tract.