title: Imbalanced expression of Vcan mRNA splice form proteins alters heart morphology and cellular protein profiles.
abstract: The fundamental importance of the proteoglycan versican to early heart formation was clearly demonstrated by the Vcan null mouse called heart defect (hdf). Total absence of the Vcan gene halts heart development at a stage prior to the heart's pulmonary/aortic outlet segment growth. This creates a problem for determining the significance of versican's expression in the forming valve precursors and vascular wall of the pulmonary and aortic roots. This study presents data from a mouse model, Vcan ((tm1Zim)), of heart defects that results from deletion of exon 7 in the Vcan gene. Loss of exon 7 prevents expression of two of the four alternative splice forms of the Vcan gene. Mice homozygous for the exon 7 deletion survive into adulthood, however, the inability to express the V2 or V0 forms of versican results in ventricular septal defects, smaller cushions/valve leaflets with diminished myocardialization and altered pulmonary and aortic outflow tracts. We correlate these phenotypic findings with a large-scale differential protein expression profiling to identify compensatory alterations in cardiac protein expression at E13.5 post coitus that result from the absence of Vcan exon 7. The Vcan ((tm1Zim)) hearts show significant changes in the relative abundance of several cytoskeletal and muscle contraction proteins including some previously associated with heart disease. These alterations define a protein fingerprint that provides insight to the observed deficiencies in pre-valvular/septal cushion mesenchyme and the stability of the myocardial phenotype required for alignment of the outflow tract with the heart ventricles.
authors.affiliation: Departments of Regenerative Medicine & Cell Biology, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Tara A
authors.initials: TA
authors.lastname: Burns
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Dours-Zimmermann
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Dieter R
authors.initials: DR
authors.lastname: Zimmermann
authors.affiliation: Departments of Regenerative Medicine & Cell Biology, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Edward L
authors.initials: EL
authors.lastname: Krug
authors.affiliation: Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Susana
authors.initials: S
authors.lastname: Comte-Walters
authors.affiliation: Departments of Regenerative Medicine & Cell Biology, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Leticia
authors.initials: L
authors.lastname: Reyes
authors.affiliation: Departments of Regenerative Medicine & Cell Biology, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Monica A
authors.initials: MA
authors.lastname: Davis
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, United States of America.
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Schey
authors.affiliation: Departments of Regenerative Medicine & Cell Biology, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: John H
authors.initials: JH
authors.lastname: Schwacke
authors.affiliation: Departments of Regenerative Medicine & Cell Biology, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Christine B
authors.initials: CB
authors.lastname: Kern
authors.affiliation: Departments of Regenerative Medicine & Cell Biology, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Corey H
authors.initials: CH
authors.lastname: Mjaatvedt
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006321:Heart / Q000033:anatomy & histology*; D006343:Heart Septal Defects / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006351:Heart Valves / Q000166:cytology / Q000473:pathology; D051379:Mice; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D040901:Proteomics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053675:Versicans / Q000235:genetics* / Q000378:metabolism
chemical_list: D020033:Protein Isoforms; D012333:RNA, Messenger; D053675:Versicans