Regulating NOTCH ligands: The role of Mind bomb1 during cardiac development and disease

Zusammenfassung

Resumen: Heart development is the result of the tightly regulated spatio-temporally embryonic processes of lineage specification, tissue patterning, cellular proliferation, differentiation and morphogenesis that ultimately lead to the adult, fully functional heart. Congenital heart disease (CHD) occurs when normal cardiac development is impaired and the structure of the heart and great vessels is abnormal. It is very frequent and approximately nine people in 1000 are born with a congenital heart defect. A great research effort is under way to understand the molecular and genetic bases of CHD, as they can be manifested in the neonate but also in the adult individual. In this work, we have used a conditional loss-of- function model of the Notch regulator Mib1, to show that Notch acting from the endocardium not only regulates early heart development, as it has been described previously, but also plays a crucial later role in the maturation of the cardiac valves and chambers. In the OFT valves, Notch regulates in a non-cell autonomous manner BMP signalling, repressing Bmp6 and cellular proliferation in the valvular mesenchyme, allowing the valves to undergo the morphogenetic processes required for their maturation. In the ventricles, Notch activity in the endocardium activated from the myocardium sends maturation signals to the myocardium, so that compact and trabecular myocardium are established by the expression of trabecular markers (Anf, Bmp10 or Cx40) and compact zone markers (Hey2, N-myc or Tbx20), allowing ventricular compaction, and thus the formation of the adult contractile wall of the heart. Absence of these Notch-dependent signals produces LVNC in humans, the third most important cardiomyopathy, with a very poorly understood etiology, characterized by prominent and excessive trabeculations, with deep recesses in the ventricular wall. LVNC manifests as depressed systolic function. Classical complications include systemic embolism, malignant arrhythmias, heart failure and sudden death. The importance of NOTCH in heart development and its impact in cardiomyopathies such as LVNC, opens a new research avenue into the identification of novel diagnostic and eventually, therapeutic targets. keywords: heart development, NOTCH, ventricular compaction, cardiac valve morphogenesis and left ventricular non compaction cardiomyopathy