Journal
DEVELOPMENT
Volume 142, Issue 23, Pages 4080-4091Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.125724
Keywords
Cardiac chamber maturation; Trabeculation; Blood flow; Cardiac contraction; Notch; Neuregulin 1; Zebrafish; Primary cilia
Categories
Funding
- National Institutes of Health [HL069768-14]
- National Institutes of Health/National Heart, Lung, and Blood Institute [R00 HL109079, 1R01HL117256, 1RO1HL54737]
- American Heart Association [15GRNT25530005, 13SDG17060010]
- Ellison Medical Foundation [AG-NS-1064-13]
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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 I (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.
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