title: The Src homology and collagen A (ShcA) adaptor protein is required for the spatial organization of the costamere/Z-disk network during heart development.
abstract: Src homology and collagen A (ShcA) is an adaptor protein that binds to tyrosine kinase receptors. Its germ line deletion is embryonic lethal with abnormal cardiovascular system formation, and its role in cardiovascular development is unknown. To investigate its functional role in cardiovascular development in mice, ShcA was deleted in cardiomyocytes and vascular smooth muscle cells by crossing ShcA flox mice with SM22a-Cre transgenic mice. Conditional mutant mice developed signs of severe dilated cardiomyopathy, myocardial infarctions, and premature death. No evidence of a vascular contribution to the phenotype was observed. Histological analysis of the heart revealed aberrant sarcomeric Z-disk and M-band structures, and misalignments of T-tubules with Z-disks. We find that not only the ErbB3/Neuregulin signaling pathway but also the baroreceptor reflex response, which have been functionally associated, are altered in the mutant mice. We further demonstrate that ShcA interacts with Caveolin-1 and the costameric protein plasma membrane Ca(2+)/calmodulin-dependent ATPase (PMCA), and that its deletion leads to abnormal dystrophin signaling. Collectively, these results demonstrate that ShcA interacts with crucial proteins and pathways that link Z-disk and costamere.
authors.affiliation: From the CNRS, UMR 7213, University of Strasbourg, 67401 Illkirch, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Mlih
authors.affiliation: From the CNRS, UMR 7213, University of Strasbourg, 67401 Illkirch, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Host
authors.affiliation: From the CNRS, UMR 7213, University of Strasbourg, 67401 Illkirch, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Martin
authors.affiliation: the Laboratory of Neurobiology and Cardiovascular Pharmacology Department, EA 7296, Federation of Translational Medicine, University of Strasbourg, 67000 Strasbourg, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Niederhoffer
authors.affiliation: the Laboratory of Neurobiology and Cardiovascular Pharmacology Department, EA 7296, Federation of Translational Medicine, University of Strasbourg, 67000 Strasbourg, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Monassier
authors.affiliation: From the CNRS, UMR 7213, University of Strasbourg, 67401 Illkirch, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Terrand
authors.affiliation: the IGBMC, INSERM U964 CNRS UMR 7104, University of Strasbourg, 67401 Illkirch, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Messaddeq
authors.affiliation: the Neuromuscular and Cardiovascular Cell Biology, Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany, the DZHK, German Centre for Cardiovascular Research, partner site, 13347 Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Radke
authors.affiliation: the Neuromuscular and Cardiovascular Cell Biology, Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany, the DZHK, German Centre for Cardiovascular Research, partner site, 13347 Berlin, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Gotthardt
authors.affiliation: From the CNRS, UMR 7213, University of Strasbourg, 67401 Illkirch, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Bruban
authors.affiliation: the CRMBM, CNRS, UMR 7339, University of Aix-Marseille, 13385 Marseille, France, and.
authors.forename: Frank
authors.initials: F
authors.lastname: Kober
authors.affiliation: the CRMBM, CNRS, UMR 7339, University of Aix-Marseille, 13385 Marseille, France, and.
authors.forename: Monique
authors.initials: M
authors.lastname: Bernard
authors.affiliation: the CREATIS-LRMN, CNRS, UMR 5220, U630 INSERM, 69621 Villeurbanne, Lyon-1 University, Lyon, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Canet-Soulas
authors.affiliation: From the CNRS, UMR 7213, University of Strasbourg, 67401 Illkirch, France.
authors.forename: Francisco
authors.initials: F
authors.lastname: Abt-Jijon
authors.affiliation: From the CNRS, UMR 7213, University of Strasbourg, 67401 Illkirch, France, philippe.boucher@unistra.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Boucher
authors.affiliation: From the CNRS, UMR 7213, University of Strasbourg, 67401 Illkirch, France, rachel.matz-westphal@unistra.fr.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Matz
mesh_terms: D000483:Alleles; D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism; D001794:Blood Pressure; D002470:Cell Survival; D054974:Costameres / Q000378:metabolism*; D016189:Dystrophin / Q000378:metabolism; D004452:Echocardiography; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology*; D008279:Magnetic Resonance Imaging; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D032383:Myocytes, Cardiac / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D010641:Phenotype; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D020893:Receptor, ErbB-3 / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
chemical_list: D016189:Dystrophin; D034741:RNA, Small Interfering; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D020893:Receptor, ErbB-3; D053499:Plasma Membrane Calcium-Transporting ATPases
keywords: Adaptor Protein; Costamere; ErbB; Gene Knockout; Heart Development; Heart Failure; Molecular Biology; ShcA; Z-disks