Heg1 and Ccm1/2 proteins control endocardial mechanosensitivity during zebrafish valvulogenesis
Abstract
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.
Article and author information
Author details
Funding
Deutsche Forschungsgemeinschaft (Excellence Cluster REBIRTH)
- Stefan Donat
Deutsche Forschungsgemeinschaft (SFB 958)
- Cécile Otten
Deutsche Forschungsgemeinschaft (Project number SE2016/7-2)
- Alessio Paolini
- Cécile Otten
- Marc Renz
Deutsche Forschungsgemeinschaft (Project number SE2016/10-1)
- Alessio Paolini
- Cécile Otten
- Marc Renz
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Handling of zebrafish was done in compliance with German and Brandenburg State law, carefully monitored by the local authority for animal protection (LUGV, Brandenburg, Germany; Animal protocol#2347-18-2015 ).
Copyright
© 2018, Donat et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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