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Heg1 and Ccm1/2 proteins control endocardial mechanosensitivity during zebrafish valvulogenesis
- 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.
Author details: | Stefan DonatORCiDGND, Marta Sofia Rocha LourencoGND, Alessio PaoliniORCiDGND, Cecile OttenORCiDGND, Marc RenzGND, Salim Abdelilah-SeyfriedORCiDGND |
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DOI: | https://doi.org/10.7554/eLife.28939 |
ISSN: | 2050-084X |
Pubmed ID: | https://pubmed.ncbi.nlm.nih.gov/29364115 |
Title of parent work (English): | eLife |
Publisher: | eLife Sciences Publications |
Place of publishing: | Cambridge |
Publication type: | Article |
Language: | English |
Date of first publication: | 2018/01/24 |
Publication year: | 2018 |
Release date: | 2022/01/28 |
Volume: | 7 |
Number of pages: | 22 |
Funding institution: | Deutsche Forschungsgmeinschafte; Deutsche ForschungsgemeinschaftGerman Research Foundation (DFG) [SFB 958, SE2016/7-2, SE2016/10-1] |
Organizational units: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Biochemie und Biologie |
DDC classification: | 5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie |
Peer review: | Referiert |
Publishing method: | Open Access / Gold Open-Access |
DOAJ gelistet | |
License (German): | CC-BY - Namensnennung 4.0 International |