Document Detail


Nf1 limits epicardial derivative expansion by regulating epithelial to mesenchymal transition and proliferation.
MedLine Citation:
PMID:  22535408     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The epicardium is the primary source of coronary vascular smooth muscle cells (cVSMCs) and fibroblasts that reside in the compact myocardium. To form these epicardial-derived cells (EPDCs), the epicardium undergoes the process of epithelial to mesenchymal transition (EMT). Although several signaling pathways have been identified that disrupt EMT, no pathway has been reported that restricts this developmental process. Here, we identify neurofibromin 1 (Nf1) as a key mediator of epicardial EMT. To determine the function of Nf1 during epicardial EMT and the formation of epicardial derivatives, cardiac fibroblasts and cVSMCs, we generated mice with a tissue-specific deletion of Nf1 in the epicardium. We found that mutant epicardial cells transitioned more readily to mesenchymal cells in vitro and in vivo. The mesothelial epicardium lost epithelial gene expression and became more invasive. Using lineage tracing of EPDCs, we found that the process of EMT occurred earlier in Nf1 mutant hearts, with an increase in epicardial cells entering the compact myocardium. Moreover, loss of Nf1 caused increased EPDC proliferation and resulted in more cardiac fibroblasts and cVSMCs. Finally, we were able to partially reverse the excessive EMT caused by loss of Nf1 by disrupting Pdgfrα expression in the epicardium. Conversely, Nf1 activation was able to inhibit PDGF-induced epicardial EMT. Our results demonstrate a regulatory role for Nf1 during epicardial EMT and provide insights into the susceptibility of patients with disrupted NF1 signaling to cardiovascular disease.
Authors:
Seung Tae Baek; Michelle D Tallquist
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-04-25
Journal Detail:
Title:  Development (Cambridge, England)     Volume:  139     ISSN:  1477-9129     ISO Abbreviation:  Development     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-05-09     Completed Date:  2012-07-20     Revised Date:  2013-06-25    
Medline Journal Info:
Nlm Unique ID:  8701744     Medline TA:  Development     Country:  England    
Other Details:
Languages:  eng     Pagination:  2040-9     Citation Subset:  IM    
Affiliation:
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Lineage / genetics
Cell Proliferation*
Epithelial-Mesenchymal Transition / physiology*
Mice
Microscopy, Fluorescence
Neurofibromin 1 / genetics,  metabolism*
Pericardium / cytology,  growth & development*
Receptor, Platelet-Derived Growth Factor alpha / metabolism
Signal Transduction / physiology*
Grant Support
ID/Acronym/Agency:
HL074257/HL/NHLBI NIH HHS; HL100401/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Neurofibromin 1; EC 2.7.10.1/Receptor, Platelet-Derived Growth Factor alpha
Comments/Corrections

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