Fibulin-1 is required during cardiac ventricular morphogenesis for versican cleavage, suppression of ErbB2 and Erk1/2 activation, and to attenuate trabecular cardiomyocyte proliferation

Research output: Contribution to journalArticle

Authors

  • Marion A. Cooley
  • Victor M. Fresco
  • Margaret E. Dorlon
  • Waleed O. Twal
  • Nathan V. Lee
  • Jeremy L. Barth
  • Christine B. Kern
  • M. Luisa Iruela-Arispe
  • W. Scott Argraves

External Institution(s)

  • Medical University of South Carolina
  • University of California at Los Angeles

Details

Original languageEnglish (US)
Pages (from-to)303-314
Number of pages12
JournalDevelopmental Dynamics
Volume241
Issue number2
StatusPublished - Feb 1 2012
Peer-reviewedYes

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. Conclusion: 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.

    Research areas

  • ADAMTS-1, Brg1, Cardiomyocyte, DPEAAE, ErbB2, Erk1/2, Fbln1, Fibulin-1, Knockout, Trabeculation, Ventricular noncompaction, Versican

Citation formats

APA

Cooley, M. A., Fresco, V. M., Dorlon, M. E., Twal, W. O., Lee, N. V., Barth, J. L., ... Argraves, W. S. (2012). Fibulin-1 is required during cardiac ventricular morphogenesis for versican cleavage, suppression of ErbB2 and Erk1/2 activation, and to attenuate trabecular cardiomyocyte proliferation. Developmental Dynamics, 241(2), 303-314. https://doi.org/10.1002/dvdy.23716

Harvard

Cooley, MA, Fresco, VM, Dorlon, ME, Twal, WO, Lee, NV, Barth, JL, Kern, CB, Iruela-Arispe, ML & Argraves, WS 2012, 'Fibulin-1 is required during cardiac ventricular morphogenesis for versican cleavage, suppression of ErbB2 and Erk1/2 activation, and to attenuate trabecular cardiomyocyte proliferation', Developmental Dynamics, vol. 241, no. 2, pp. 303-314. https://doi.org/10.1002/dvdy.23716