Heg1 and Ccm1/2 proteins control endocardial mechanosensitivity during zebrafish valvulogenesis
- Potsdam University, Germany
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
Salim Abdelilah-Seyfried
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.
Reviewing Editor
- Deborah Yelon, University of California, San Diego, United States
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 ).
Version history
- Received: May 23, 2017
- Accepted: January 24, 2018
- Accepted Manuscript published: January 24, 2018 (version 1)
- Version of Record published: February 1, 2018 (version 2)
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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Heg1 and Ccm1/2 proteins control endocardial mechanosensitivity during zebrafish valvulogenesis
eLife 7:e28939.
https://doi.org/10.7554/eLife.28939
Further reading
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Large-scale cell flow characterizes gastrulation in animal development. In amniote gastrulation, particularly in avian gastrula, a bilateral vortex-like counter-rotating cell flow, called ‘polonaise movements’, appears along the midline. Here, through experimental manipulations, we addressed relationships between the polonaise movements and morphogenesis of the primitive streak, the earliest midline structure in amniotes. Suppression of the Wnt/planar cell polarity (PCP) signaling pathway maintains the polonaise movements along a deformed primitive streak. Mitotic arrest leads to diminished extension and development of the primitive streak and maintains the early phase of the polonaise movements. Ectopically induced Vg1, an axis-inducing morphogen, generates the polonaise movements, aligned to the induced midline, but disturbs the stereotypical cell flow pattern at the authentic midline. Despite the altered cell flow, induction and extension of the primitive streak are preserved along both authentic and induced midlines. Finally, we show that ectopic axis-inducing morphogen, Vg1, is capable of initiating the polonaise movements without concomitant PS extension under mitotic arrest conditions. These results are consistent with a model wherein primitive streak morphogenesis is required for the maintenance of the polonaise movements, but the polonaise movements are not necessarily responsible for primitive streak morphogenesis. Our data describe a previously undefined relationship between the large-scale cell flow and midline morphogenesis in gastrulation.
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- Physics of Living Systems
Geometric criteria can be used to assess whether cell intercalation is active or passive during the convergent extension of tissue.
