Heg1 and Ccm1/2 proteins control endocardial mechanosensitivity during zebrafish valvulogenesis
- Donat, S., Lourenço, M., Paolini, A., Otten, C., Renz, M., Abdelilah-Seyfried, S.
- eLIFE 7: e28939 (Journal)
- Registered Authors
- Abdelilah-Seyfried, Salim, Paolini, Alessio
- developmental biology, stem cells, zebrafish
- MeSH Terms
- Endothelial Cells/physiology*
- Heart Valves/embryology*
- Kruppel-Like Transcription Factors/metabolism*
- Mechanotransduction, Cellular*
- Membrane Glycoproteins/metabolism*
- Microtubule-Associated Proteins/metabolism*
- Zebrafish Proteins/metabolism*
- 29364115 Full text @ Elife
Donat, S., Lourenço, M., Paolini, A., Otten, C., Renz, M., Abdelilah-Seyfried, S. (2018) Heg1 and Ccm1/2 proteins control endocardial mechanosensitivity during zebrafish valvulogenesis. eLIFE. 7:e28939.
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.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes