Heg1 and Ccm1/2 proteins control endocardial mechanosensitivity during zebrafish valvulogenesis

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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.

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Stefan Donat

Institute of Biochemistry and Biology, Potsdam University, Potsdam, Germany

Competing interests
The authors declare that no competing interests exist.
Marta Lourenço

Institute of Biochemistry and Biology, Potsdam University, Potsdam, Germany

Competing interests
The authors declare that no competing interests exist.
Alessio Paolini

Institute of Biochemistry and Biology, Potsdam University, Potsdam, Germany

Competing interests
The authors declare that no competing interests exist.
Cécile Otten

Institute of Biochemistry and Biology, Potsdam University, Potsdam, Germany

Competing interests
The authors declare that no competing interests exist.
Marc Renz

Institute of Biochemistry and Biology, Potsdam University, Potsdam, Germany

Competing interests
The authors declare that no competing interests exist.
Salim Abdelilah-Seyfried

Institute of Biochemistry and Biology, Potsdam University, Potsdam, Germany

For correspondence
salim.seyfried@uni-potsdam.de

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-3183-3841

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

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.