TY  - JOUR
A1  - Donat, Stefan
A1  - Lourenco, Marta Sofia Rocha
A1  - Paolini, Alessio
A1  - Otten, Cecile
A1  - Renz, Marc
A1  - Abdelilah-Seyfried, Salim
T1  - Heg1 and Ccm1/2 proteins control endocardial mechanosensitivity during zebrafish valvulogenesis
JF  - eLife
N2  - Endothelial cells respond to different levels of fluid shear stress through adaptations of their mechanosensitivity. Currently, we lack a good understanding of how this contributes to sculpting of the cardiovascular system. Cerebral cavernous malformation (CCM) is an inherited vascular disease that occurs when a second somatic mutation causes a loss of CCM1/KRIT1, CCM2, or CCM3 proteins. Here, we demonstrate that zebrafish Krit1 regulates the formation of cardiac valves. Expression of heg1, which encodes a binding partner of Krit1, is positively regulated by blood-flow. In turn, Heg1 stabilizes levels of Krit1 protein, and both Heg1 and Krit1 dampen expression levels of klf2a, a major mechanosensitive gene. Conversely, loss of Krit1 results in increased expression of klf2a and notch1b throughout the endocardium and prevents cardiac valve leaflet formation. Hence, the correct balance of blood-flow-dependent induction and Krit1 protein mediated repression of klf2a and notch1b ultimately shapes cardiac valve leaflet morphology.
Y1  - 2018
U6  - https://doi.org/10.7554/eLife.28939
SN  - 2050-084X
VL  - 7
PB  - eLife Sciences Publications
CY  - Cambridge
ER  -