Document Detail

Integration of a Notch-dependent mesenchymal gene program and Bmp2-driven cell invasiveness regulates murine cardiac valve formation.
MedLine Citation:
PMID:  20890042     Owner:  NLM     Status:  MEDLINE    
Cardiac valve formation is crucial for embryonic and adult heart function. Valve malformations constitute the most common congenital cardiac defect, but little is known about the molecular mechanisms regulating valve formation and homeostasis. Here, we show that endocardial Notch1 and myocardial Bmp2 signal integration establish a valve-forming field between 2 chamber developmental domains. Patterning occurs through the activation of endocardial epithelial-to-mesenchymal transition (EMT) exclusively in prospective valve territories. Mice with constitutive endocardial Notch1 activity ectopically express Hey1 and Heyl. They also display an activated mesenchymal gene program in ventricles and a partial (noninvasive) EMT in vitro that becomes invasive upon BMP2 treatment. Snail1, TGF-β2, or Notch1 inhibition reduces BMP2-induced ventricular transformation and invasion, whereas BMP2 treatment inhibits endothelial Gsk3β, stabilizing Snail1 and promoting invasiveness. Integration of Notch and Bmp2 signals is consistent with Notch1 signaling being attenuated after myocardial Bmp2 deletion. Notch1 activation in myocardium extends Hey1 expression to nonchamber myocardium, represses Bmp2, and impairs EMT. In contrast, Notch deletion abrogates endocardial Hey gene transcription and extends Bmp2 expression to the ventricular endocardium. This embryonic Notch1-Bmp2-Snail1 relationship may be relevant in adult valve disease, in which decreased NOTCH signaling causes valve mesenchyme cell formation, fibrosis, and calcification.
Luis Luna-Zurita; Belén Prados; Joaquim Grego-Bessa; Guillermo Luxán; Gonzalo del Monte; Alberto Benguría; Ralf H Adams; José María Pérez-Pomares; José Luis de la Pompa
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-09-20
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  120     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-10-05     Completed Date:  2010-11-10     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3493-507     Citation Subset:  AIM; IM    
Laboratorio de Biología Celular y del Desarrollo, Departamento de Biología del Desarrollo Cardiovascular, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
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MeSH Terms
Basic Helix-Loop-Helix Transcription Factors / analysis
Bone Morphogenetic Protein 2 / physiology*
Cell Cycle Proteins / analysis
Epithelial Cells / pathology
Gene Expression Regulation, Developmental
Heart Valves / embryology*
Mesoderm / metabolism*,  pathology
Receptor, Notch1 / physiology*
Repressor Proteins / analysis
Signal Transduction
Transcription Factors / physiology
Transforming Growth Factor beta2 / physiology
Reg. No./Substance:
0/Basic Helix-Loop-Helix Transcription Factors; 0/Bmp2 protein, mouse; 0/Bone Morphogenetic Protein 2; 0/Cell Cycle Proteins; 0/Hey1 protein, mouse; 0/Hey2 protein, mouse; 0/Notch1 protein, mouse; 0/Receptor, Notch1; 0/Repressor Proteins; 0/Transcription Factors; 0/Transforming Growth Factor beta2; 0/snail family transcription factors

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