title: Cardiac contraction activates endocardial Notch signaling to modulate chamber maturation in zebrafish.
abstract: 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.
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA McAllister Heart Institute, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Leigh Ann
authors.initials: LA
authors.lastname: Samsa
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA McAllister Heart Institute, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Givens
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA McAllister Heart Institute, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 7BN, UK.
authors.forename: Eleni
authors.initials: E
authors.lastname: Tzima
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim 61231, Germany.
authors.forename: Didier Y R
authors.initials: DY
authors.lastname: Stainier
authors.affiliation: McAllister Heart Institute, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Qian
authors.affiliation: McAllister Heart Institute, UNC School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94158, USA Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA jiandong_liu@med.unc.edu.
authors.forename: Jiandong
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002923:Cilia / Q000378:metabolism; D036388:Ephrin-B2 / Q000378:metabolism; D004843:Epistasis, Genetic; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology*; D006352:Heart Ventricles / Q000196:embryology; D017403:In Situ Hybridization; D020890:Neuregulin-1 / Q000378:metabolism; D009841:Oligonucleotides / Q000235:genetics; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000378:metabolism*
chemical_list: D036388:Ephrin-B2; D020890:Neuregulin-1; D009841:Oligonucleotides; D051880:Receptors, Notch; D029961:Zebrafish Proteins
keywords: Blood flow; Cardiac chamber maturation; Cardiac contraction; Neuregulin 1; Notch; Primary cilia; Trabeculation; Zebrafish