Signaling in cardiac development, disease & regeneration.
Valves. In the early valve region, Notch in concert with the myocardial signal Bmp2, drives the regionalized endocardial EMT that will lead to the formation of the cardiac valve primordium (PMID: 14701881, 20890042, 29853617). Later in development, endocardial Notch regulates the proliferation of valve mesenchyme cells, via a non-cell autonomous mechanism mediated by Hbegf. Notch signaling abrogation leads to the formation of dysmorphic aortic valves, that show an abnormal bicuspid structure (BAV; PMID: 27056911), supporting data identifying NOTCH1 mutations in BAV families (PMID: 16025100). Our work on the adult heart has established a pioneering mouse model of aortic valve stenosis (PMID: 21493891) and elucidated the fundamental role of Notch in promoting inflammation during atherosclerosis (PMID: 27496872).
Ventricles. Endocardial Dll4-Notch1 signaling favored by the glycosyltransferase Fringe (MFng) is crucial for the formation of trabeculae (PMID: 17336907, 25497097). Jag1/Jag2-Notch1 regulates the later process of compaction that will give rise to the mature, functional ventricular walls (PMID: 26641715). Mutations in the ubiquitin ligase gene MINDBOMB1 (MIB1), which is essential for Notch ligand activity, cause left ventricular non-compaction cardiomyopathy (LVNC) cardiomyopathy in mice and men (PMID: 23314057). Coronaries are essential for myocardial growth, compaction and heart function. We have found that coronary arterial precursors are specified in the sinus venosus through a Jag1-Dll4 interplay with Notch and coronary arterial differentiation depends on a Dll4-Jag1-EphrinB2 signaling cascade (PMID: 21311046, 31789590).
Zebrafish heart regeneration. We have recently shown that Caveolin-1 and caveolae are required in the adult zebrafish heart for cardiac cell contractility and prevention of heart stiffness and functional decline (PMID: 32733088). Previously, we showed that during zebrafish fin regeneration Notch regulates blastema proliferation and prevents differentiation (PMID: 23344707), while in the regenerating zebrafish heart, Notch restricts inflammation and expression of the serine protease inhibitor serpine1 (PMID: 28242613).
- Molecular mechanisms of cardiac chamber and valve development and disease. 01/06/2020-31/12/2023. PID2019-104776RB-I00. Funding Agency: Ministerio de Ciencia e Innovación.
- Cell Therapy Research Network. Funding Agency: Instituto de Salud Carlos III. Ref.: RD16/0011/0021. 2017-2021.
- CIBER Cardiovascular. Instituto de Salud Carlos III. Ref.: CB16/11/00399. 2017-2021.