Focal adhesion kinase is required for neural crest cell morphogenesis during mouse cardiovascular development
Ainara Vallejo-Illarramendi, … , Keling Zang, Louis F. Reichardt
Ainara Vallejo-Illarramendi, … , Keling Zang, Louis F. Reichardt
Published July 1, 2009
Citation Information: J Clin Invest. 2009;119(8):2218-2230. https://doi.org/10.1172/JCI38194.
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Focal adhesion kinase is required for neural crest cell morphogenesis during mouse cardiovascular development

Abstract

Neural crest cells (NCCs) participate in the remodeling of the cardiac outflow tract and pharyngeal arch arteries during cardiovascular development. Focal adhesion kinase (FAK) mediates signal transduction by integrin and growth factor receptors, each of which is important for normal cardiovascular development. To investigate the role of FAK in NCC morphogenesis, we deleted it in murine NCCs using Wnt1cre, yielding craniofacial and cardiovascular malformations resembling those observed in individuals with DiGeorge syndrome. In these mice, we observed normal cardiac NCC migration but reduced differentiation into smooth muscle within the aortic arch arteries and impaired cardiac outflow tract rotation, which resulted in a dextroposed aortic root. Moreover, within the conotruncal cushions, Fak-deficient NCCs formed a less organized mesenchyme, with reduced expression of perlecan and semaphorin 3C, and exhibited disorganized F-actin stress fibers within the aorticopulmonary septum. Additionally, absence of Fak resulted in reduced in vivo phosphorylation of Crkl and Erk1/2, components of a signaling pathway essential for NCC development. Consistent with this, both TGF-β and FGF induced FAK and Crkl phosphorylation in control but not Fak-deficient NCCs in vitro. Our results indicate that FAK plays an essential role in cardiac outflow tract development by promoting the activation of molecules such as Crkl and Erk1/2.

Authors

Ainara Vallejo-Illarramendi, Keling Zang, Louis F. Reichardt

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Figure 2

Normal neural crest migration in conditional Fak mutant embryos.

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Normal neural crest migration in conditional Fak mutant embryos. (A)...
(A) Whole mounts of E9.5 and E10.5 X-gal–stained embryos. The right column shows sagittal sections of E10.5 embryos stained with Fast Red. Arrows indicate colonization of the outflow tract by cardiac NCCs (blue). (B) Whole mounts of E12.5 X-gal–stained hearts. Asterisks show positions of the great arteries in mutant embryos, showing misalignment of the great arteries and abnormal aorticopulmonary communication (APC). The left column shows frontal views; the middle column shows right views; the right column shows frontal histological sections of the hearts. (C) Frontal cryostat sections of E11 embryos at distal outflow tract levels. Cardiac NCCs (green) are able to colonize the outflow tract of mutants and form conotruncal cushions (c). (D) No significant difference was found in the number of NCCs in E11 control and mutant outflow tracts. This analysis was performed using 10 serial sections, 30 μm apart, with locations matched between control and mutant littermates. A minimal conotruncal cushion area of 0.22 mm2 was analyzed from each embryo. Data are expressed as mean ± SD. Scale bars: 250 μm (A); 500 μm (B); 100 μm (C).