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.
Verfasserangaben: | 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 |
Titel des übergeordneten Werks (Englisch): | eLife |
Verlag: | eLife Sciences Publications |
Verlagsort: | Cambridge |
Publikationstyp: | Wissenschaftlicher Artikel |
Sprache: | Englisch |
Datum der Erstveröffentlichung: | 24.01.2018 |
Erscheinungsjahr: | 2018 |
Datum der Freischaltung: | 28.01.2022 |
Band: | 7 |
Seitenanzahl: | 22 |
Fördernde Institution: | Deutsche Forschungsgmeinschafte; Deutsche ForschungsgemeinschaftGerman Research Foundation (DFG) [SFB 958, SE2016/7-2, SE2016/10-1] |
Organisationseinheiten: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Biochemie und Biologie |
DDC-Klassifikation: | 5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie |
Peer Review: | Referiert |
Publikationsweg: | Open Access / Gold Open-Access |
DOAJ gelistet | |
Lizenz (Deutsch): | CC-BY - Namensnennung 4.0 International |