ZFIN ID: ZDB-PUB-180125-6
Heg1 and Ccm1/2 proteins control endocardial mechanosensitivity during zebrafish valvulogenesis
Donat, S., Lourenço, M., Paolini, A., Otten, C., Renz, M., Abdelilah-Seyfried, S.
Date: 2018
Source: eLIFE   7: e28939 (Journal)
Registered Authors: Abdelilah-Seyfried, Salim, Paolini, Alessio
Keywords: developmental biology, stem cells, zebrafish
MeSH Terms:
  • Animals
  • Endothelial Cells/physiology*
  • Heart Valves/embryology*
  • Kruppel-Like Transcription Factors/metabolism*
  • Mechanotransduction, Cellular*
  • Membrane Glycoproteins/metabolism*
  • Microtubule-Associated Proteins/metabolism*
  • Zebrafish/embryology*
  • Zebrafish Proteins/metabolism*
PubMed: 29364115 Full text @ Elife
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.