Integration of a Notch-dependent mesenchymal gene program and Bmp2-driven cell invasiveness regulates murine cardiac valve formation
Open Access
- 1 October 2010
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 120 (10), 3493-3507
- https://doi.org/10.1172/jci42666
Abstract
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.Keywords
This publication has 57 references indexed in Scilit:
- The Canonical Notch Signaling Pathway: Unfolding the Activation MechanismCell, 2009
- Bone morphogenetic protein 2 induces pulmonary angiogenesis via Wnt–β-catenin and Wnt–RhoA–Rac1 pathwaysThe Journal of cell biology, 2009
- Slug is a direct Notch target required for initiation of cardiac cushion cellularizationThe Journal of cell biology, 2008
- Notch signaling mediates hypoxia-induced tumor cell migration and invasionProceedings of the National Academy of Sciences of the United States of America, 2008
- Monitoring Notch1 activity in development: Evidence for a feedback regulatory loopDevelopmental Dynamics, 2007
- Notch Signaling Is Essential for Ventricular Chamber DevelopmentDevelopmental Cell, 2007
- NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growthProceedings of the National Academy of Sciences of the United States of America, 2006
- Bmp2 instructs cardiac progenitors to form the heart-valve-inducing fieldDevelopmental Biology, 2006
- Mutations in NOTCH1 cause aortic valve diseaseNature, 2005
- Tie2-Cre Transgenic Mice: A New Model for Endothelial Cell-Lineage Analysis in VivoDevelopmental Biology, 2001