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Deletion of integrin-linked kinase from neural crest cells in mice results in aortic aneurysms and embryonic lethality

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...

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Autores principales: Arnold, Thomas D., Zang, Keling, Vallejo-Illarramendi, Ainara
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Company of Biologists Limited 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759340/
https://www.ncbi.nlm.nih.gov/pubmed/23744273
http://dx.doi.org/10.1242/dmm.011866
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author Arnold, Thomas D.
Zang, Keling
Vallejo-Illarramendi, Ainara
author_facet Arnold, Thomas D.
Zang, Keling
Vallejo-Illarramendi, Ainara
author_sort Arnold, Thomas D.
collection PubMed
description 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.
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spelling pubmed-37593402013-09-16 Deletion of integrin-linked kinase from neural crest cells in mice results in aortic aneurysms and embryonic lethality Arnold, Thomas D. Zang, Keling Vallejo-Illarramendi, Ainara Dis Model Mech Research Article 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. The Company of Biologists Limited 2013-09 2013-06-05 /pmc/articles/PMC3759340/ /pubmed/23744273 http://dx.doi.org/10.1242/dmm.011866 Text en © 2013. Published by The Company of Biologists Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Research Article
Arnold, Thomas D.
Zang, Keling
Vallejo-Illarramendi, Ainara
Deletion of integrin-linked kinase from neural crest cells in mice results in aortic aneurysms and embryonic lethality
title Deletion of integrin-linked kinase from neural crest cells in mice results in aortic aneurysms and embryonic lethality
title_full Deletion of integrin-linked kinase from neural crest cells in mice results in aortic aneurysms and embryonic lethality
title_fullStr Deletion of integrin-linked kinase from neural crest cells in mice results in aortic aneurysms and embryonic lethality
title_full_unstemmed Deletion of integrin-linked kinase from neural crest cells in mice results in aortic aneurysms and embryonic lethality
title_short Deletion of integrin-linked kinase from neural crest cells in mice results in aortic aneurysms and embryonic lethality
title_sort deletion of integrin-linked kinase from neural crest cells in mice results in aortic aneurysms and embryonic lethality
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759340/
https://www.ncbi.nlm.nih.gov/pubmed/23744273
http://dx.doi.org/10.1242/dmm.011866
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