Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

Congenital heart disease often features structural abnormalities that emerge during development. Accumulating evidence indicates a crucial role for cardiac contraction and the resulting fluid forces in shaping the heart, yet the molecular basis of this function is largely unknown. Using the zebrafish as a model of early heart development, we investigated the role of cardiac contraction in chamber maturation, focusing on the formation of muscular protrusions called trabeculae. By genetic and pharmacological ablation of cardiac contraction, we showed that cardiac contraction is required for trabeculation through its role in regulating notch1b transcription in the ventricular endocardium. We also showed that Notch1 activation induces expression of ephrin b2a (efnb2a) and neuregulin 1 (nrg1) in the endocardium to promote trabeculation and that forced Notch activation in the absence of cardiac contraction rescues efnb2a and nrg1 expression. Using in vitro and in vivo systems, we showed that primary cilia are important mediators of fluid flow to stimulate Notch expression. Together, our findings describe an essential role for cardiac contraction-responsive transcriptional changes in endocardial cells to regulate cardiac chamber maturation.

Original publication

DOI

10.1242/dev.125724

Type

Journal article

Journal

Development

Publication Date

01/12/2015

Volume

142

Pages

4080 - 4091

Keywords

Blood flow, Cardiac chamber maturation, Cardiac contraction, Neuregulin 1, Notch, Primary cilia, Trabeculation, Zebrafish, Animals, Cells, Cultured, Cilia, Ephrin-B2, Epistasis, Genetic, Gene Expression Profiling, Gene Expression Regulation, Developmental, Heart, Heart Ventricles, In Situ Hybridization, Neuregulin-1, Oligonucleotides, Receptors, Notch, Signal Transduction, Time Factors, Zebrafish, Zebrafish Proteins