title: Deletion of integrin-linked kinase from neural crest cells in mice results in aortic aneurysms and embryonic lethality.
abstract: Neural crest cells (NCCs) participate in the remodeling of the cardiac outflow tract and pharyngeal arch arteries during cardiovascular development. Integrin-linked kinase (ILK) is a serine/threonine kinase and a major regulator of integrin signaling. It links integrins to the actin cytoskeleton and recruits other adaptor molecules into a large complex to regulate actin dynamics and integrin function. Using the Cre-lox system, we deleted Ilk from NCCs of mice to investigate its role in NCC morphogenesis. The resulting mutants developed a severe aneurysmal arterial trunk that resulted in embryonic lethality during late gestation. Ilk mutants showed normal cardiac NCC migration but reduced differentiation into smooth muscle within the aortic arch arteries and the outflow tract. Within the conotruncal cushions, Ilk-deficient NCCs exhibited disorganization of F-actin stress fibers and a significantly rounder morphology, with shorter cellular projections. Additionally, absence of ILK resulted in reduced in vivo phosphorylation of Smad3 in NCCs, which correlated with reduced αSMA levels. Our findings resemble those seen in Pinch1 and β1 integrin conditional mutant mice, and therefore support that, in neural crest-derived cells, ILK and Pinch1 act as cytoplasmic effectors of β1 integrin in a pathway that protects against aneurysms. In addition, our conditional Ilk mutant mice might prove useful as a model to study aortic aneurysms caused by reduced Smad3 signaling, as occurs in the newly described aneurysms-osteoarthritis syndrome, for example.
authors.affiliation: Department of Pediatrics, University of California, San Francisco, CA 94143, USA.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Arnold
authors.forename: Keling
authors.initials: K
authors.lastname: Zang
authors.forename: Ainara
authors.initials: A
authors.lastname: Vallejo-Illarramendi
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D001013:Aorta, Thoracic / Q000002:abnormalities / Q000196:embryology / Q000473:pathology; D001014:Aortic Aneurysm / Q000201:enzymology* / Q000473:pathology*; D018376:Cardiovascular Abnormalities / Q000196:embryology / Q000473:pathology; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D019465:Craniofacial Abnormalities / Q000196:embryology / Q000473:pathology; D020964:Embryo Loss / Q000201:enzymology* / Q000473:pathology; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000473:pathology; D017353:Gene Deletion; D019426:Integrases / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009024:Morphogenesis; D009432:Neural Crest / Q000201:enzymology* / Q000473:pathology*; D009928:Organ Specificity; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000378:metabolism; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D000099200:Scaffold Protein ILK
chemical_list: D019426:Integrases; D017346:Protein Serine-Threonine Kinases; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; D000099200:Scaffold Protein ILK; C045073:Cre recombinase