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...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2018-01-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/28939 |
| _version_ | 1811201665449066496 |
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| author | Stefan Donat Marta Lourenço Alessio Paolini Cécile Otten Marc Renz Salim Abdelilah-Seyfried |
| author_facet | Stefan Donat Marta Lourenço Alessio Paolini Cécile Otten Marc Renz Salim Abdelilah-Seyfried |
| author_sort | Stefan Donat |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T02:24:41Z |
| format | Article |
| id | doaj.art-ba003a4d16e341049fdc2a9f71e02c9f |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:24:41Z |
| publishDate | 2018-01-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-ba003a4d16e341049fdc2a9f71e02c9f2022-12-22T03:52:01ZengeLife Sciences Publications LtdeLife2050-084X2018-01-01710.7554/eLife.28939Heg1 and Ccm1/2 proteins control endocardial mechanosensitivity during zebrafish valvulogenesisStefan Donat0https://orcid.org/0000-0003-3901-3733Marta Lourenço1Alessio Paolini2https://orcid.org/0000-0001-7002-7303Cécile Otten3https://orcid.org/0000-0002-8230-7350Marc Renz4Salim Abdelilah-Seyfried5https://orcid.org/0000-0003-3183-3841Institute of Biochemistry and Biology, Potsdam University, Potsdam, Germany; Institute of Molecular Biology, Hannover Medical School, Hannover, GermanyInstitute of Biochemistry and Biology, Potsdam University, Potsdam, GermanyInstitute of Biochemistry and Biology, Potsdam University, Potsdam, GermanyInstitute of Biochemistry and Biology, Potsdam University, Potsdam, GermanyInstitute of Biochemistry and Biology, Potsdam University, Potsdam, GermanyInstitute of Biochemistry and Biology, Potsdam University, Potsdam, Germany; Institute of Molecular Biology, Hannover Medical School, Hannover, GermanyEndothelial 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.https://elifesciences.org/articles/28939CCMheartcardiac valvesKLF2endocardiumVE-cadherin |
| spellingShingle | Stefan Donat Marta Lourenço Alessio Paolini Cécile Otten Marc Renz Salim Abdelilah-Seyfried Heg1 and Ccm1/2 proteins control endocardial mechanosensitivity during zebrafish valvulogenesis eLife CCM heart cardiac valves KLF2 endocardium VE-cadherin |
| title | Heg1 and Ccm1/2 proteins control endocardial mechanosensitivity during zebrafish valvulogenesis |
| title_full | Heg1 and Ccm1/2 proteins control endocardial mechanosensitivity during zebrafish valvulogenesis |
| title_fullStr | Heg1 and Ccm1/2 proteins control endocardial mechanosensitivity during zebrafish valvulogenesis |
| title_full_unstemmed | Heg1 and Ccm1/2 proteins control endocardial mechanosensitivity during zebrafish valvulogenesis |
| title_short | Heg1 and Ccm1/2 proteins control endocardial mechanosensitivity during zebrafish valvulogenesis |
| title_sort | heg1 and ccm1 2 proteins control endocardial mechanosensitivity during zebrafish valvulogenesis |
| topic | CCM heart cardiac valves KLF2 endocardium VE-cadherin |
| url | https://elifesciences.org/articles/28939 |
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