title: Fibulin-1 is required during cardiac ventricular morphogenesis for versican cleavage, suppression of ErbB2 and Erk1/2 activation, and to attenuate trabecular cardiomyocyte proliferation.
abstract: BACKGROUND
  Trabeculation is an integral component of cardiac ventricular morphogenesis and is dependent on the matrix metalloproteinase, ADAMTS1. A substrate of ADAMTS1 is the proteoglycan versican which is expressed in the developing ventricle and which has been implicated in trabeculation. Fibulin-1 is a versican and ADAMTS1-binding extracellular matrix protein required for ventricular morphogenesis. Here we investigated the involvement of fibulin-1 in ADAMTS1-mediated cleavage of versican in vitro, and the involvement of fibulin-1 in versican cleavage in ventricular morphogenesis.
  
  
  RESULTS
  We show that fibulin-1 is a cofactor for ADAMTS1-dependent in vitro cleavage of versican V1, yielding a 70-kDa amino-terminal fragment. Furthermore, fibulin-1-deficiency in mice was found to cause a significant reduction (>90%) in ventricular levels of the 70-kDa versican V1 cleavage product and a 2-fold increase in trabecular cardiomyocyte proliferation. Decreased versican V1 cleavage and augmented trabecular cardiomyocyte proliferation in fibulin-1 null hearts is accompanied by increased ventricular activation of ErbB2 and Erk1/2. By contrast, versican deficiency was found to lead to decreased cardiomyocyte proliferation and reduced ventricular trabeculation.
  
  
  CONCLUSIONS
  We conclude that fibulin-1 regulates versican-dependent events in ventricular morphogenesis by promoting ADAMTS1 cleavage of versican leading to suppression of trabecular cardiomyocyte proliferation mediated by the ErbB2-Map kinase pathway.
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, South Carolina 29425-2204, USA.
authors.forename: Marion A
authors.initials: MA
authors.lastname: Cooley
authors.forename: Victor M
authors.initials: VM
authors.lastname: Fresco
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Dorlon
authors.forename: Waleed O
authors.initials: WO
authors.lastname: Twal
authors.forename: Nathan V
authors.initials: NV
authors.lastname: Lee
authors.forename: Jeremy L
authors.initials: JL
authors.lastname: Barth
authors.forename: Christine B
authors.initials: CB
authors.lastname: Kern
authors.forename: M Luisa
authors.initials: ML
authors.lastname: Iruela-Arispe
authors.forename: W Scott
authors.initials: WS
authors.lastname: Argraves
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000071097:ADAMTS1 Protein; D000818:Animals; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D006352:Heart Ventricles / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009024:Morphogenesis; D032383:Myocytes, Cardiac / Q000502:physiology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism
chemical_list: D051722:ADAM Proteins; D000071097:ADAMTS1 Protein; D002135:Calcium-Binding Proteins; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D018719:Erb-b2 Receptor Tyrosine Kinases; C060820:fibulin; C524056:Erbb2 protein, mouse; C486323:Adamts1 protein, mouse