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Integration of a Notch-dependent mesenchymal gene program and Bmp2-driven cell invasiveness regulates murine cardiac valve formation
Luis Luna-Zurita, … , José María Pérez-Pomares, José Luis de la Pompa
Luis Luna-Zurita, … , José María Pérez-Pomares, José Luis de la Pompa
Published September 20, 2010
Citation Information: J Clin Invest. 2010;120(10):3493-3507. https://doi.org/10.1172/JCI42666.
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Research Article Development

Integration of a Notch-dependent mesenchymal gene program and Bmp2-driven cell invasiveness regulates murine cardiac valve formation

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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.

Authors

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

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Figure 1

E9.5 Tie2-Cre;N1ICD mice ectopically express mesenchyme genes in chamber endocardium.

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E9.5 Tie2-Cre;N1ICD mice ectopically express mesenchyme genes in chamber...
(A) WT and Tie2-Cre;N1ICD embryos. Dotted lines indicate C and D section planes. (B) Endocardial EGFP expression in a Tie2-Cre;N1ICD embryo. at, atrium. (C and D) SEM images of longitudinal WT (C) and Tie2-Cre;N1ICD (D) heart sections. (E and F) Details of AVC in WT (E) and Tie2-Cre;N1ICD hearts (F). Arrows, mesenchymal cells. (G) Semiquantitative RT-PCR analysis in hearts. (H) Snail1 Western blot. (I–P) WISH, heart details. Arrowheads, AVC myocardium; thin arrows, AVC endocardium; thick arrows, ventricular endocardium. (I) Tgfb2 expression in WT AVC myocardium and endocardium (bracket). (J) Normal Tgfb2 expression in AVC and ectopic expression in ventricular endocardium of Tie2-Cre;N1ICD embryos. (K and L) WT mice express Snail1 in AVC endocardium and mesenchyme (K); Tie2-Cre;N1ICD embryos show ectopic expression in ventricular endocardium (L). Tie2-Cre;N1ICD hearts also show ectopic ventricular expression of Snail2 (N) and Twist2 (P). (Q–V) Snail1 expression (red) in E9.5 heart. Nuclei are DAPI counterstained (blue). (Q) General view of an E9.5 WT heart. (S) Detail of AVC region. Arrows, nuclear Snail1 in endocardial and mesenchyme cells. (U) Detail of LV region with an ENC weakly expressing Snail1 (arrow). (R) General view of Tie2-Cre;N1ICD heart. (T) Detail of AVC. Arrows, nuclear Snail1 staining in endocardium and mesenchyme. (V) Ectopic Snail1 staining in ventricular endocardium. Scale bars: 100 μm (A and B); 125 μm (C and D); 20 μm (E and F); 10 μm (I–P); 30 μm (Q and R); 20 μm (S–V).

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