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Research Article
Fibulin-1 is required during cardiac ventricular morphogenesis for versican cleavage, suppression of ErbB2 and Erk1/2 activation, and to attenuate trabecular cardiomyocyte proliferation
Article first published online: 19 DEC 2011
DOI: 10.1002/dvdy.23716
Copyright © 2011 Wiley Periodicals, Inc.
Additional Information
How to Cite
Cooley, M. A., Fresco, V. M., Dorlon, M. E., Twal, W. O., Lee, N. V., Barth, J. L., Kern, C. B., Iruela-Arispe, M. L. and 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: 303–314. doi: 10.1002/dvdy.23716
Publication History
- Issue published online: 24 JAN 2012
- Article first published online: 19 DEC 2011
- Accepted manuscript online: 6 DEC 2011 02:26PM EST
- Manuscript Accepted: 23 NOV 2011
Funded by
- National Institutes of Health. Grant Numbers: HL095067, HL085618
- American Heart Association. Grant Numbers: AHA0755346U, 10SDG2610168
- South Carolina Clinical and Translational Research Institute (SCTR) Clinical and Translational Science Award. Grant Number: RR029881
- Abstract
- Article
- References
- Cited By
Keywords:
- trabeculation;
- ventricular noncompaction;
- versican;
- fibulin-1;
- Fbln1;
- ADAMTS-1;
- ErbB2;
- Brg1;
- Erk1/2;
- DPEAAE;
- cardiomyocyte;
- knockout
Key findings:
Fibulin-1 promotes ADAMTS1-mediated cleavage of versican.
Fibulin-1 deficient embryonic cardiac ventricles have reduced levels of the 70-kDa amino-terminal fragment of versican V1 containing a carboxy terminal DPEAAE sequence.
Fibulin-1 deficient embryonic cardiac ventricles have increased trabecular cardiomyocyte proliferation.
Fibulin-1 deficient embryonic cardiac ventricles have increased levels of ErbB2 and Erk1/2 activation.
Hearts from versicanhdf/hdf embryos lack versican V0/V1 and show a lack of trabeculae.
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. Developmental Dynamics 241:303–314, 2012. © 2011 Wiley Periodicals, Inc.