Focal adhesion kinase is required for neural crest cell morphogenesis during mouse cardiovascular development.
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-beta 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.
Vallejo-Illarramendi
Ainara
A
Department of Physiology, UCSF, San Francisco, California 94158-2611, USA. ainaravallejo@yahoo.es
Zang
Keling
K
Reichardt
Louis F
LF
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement; D019465:Craniofacial Abnormalities / Q000209:etiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology*; D006321:Heart / Q000196:embryology*; D006330:Heart Defects, Congenital / Q000209:etiology; D019012:Integrin beta1 / Q000502:physiology; D051379:Mice; D009024:Morphogenesis; D009154:Mutation; D009432:Neural Crest / Q000166:cytology / Q000196:embryology*; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; C082869:CRKL protein; D019012:Integrin beta1; D009687:Nuclear Proteins; D051416:Focal Adhesion Protein-Tyrosine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases