Our goals are to identify and understand the function of genes involved in heart development and function. We are conducting these studies in zebrafish, a vertebrate model system well suited to embryological and genetic studies. Over the past few years, we have investigated topics such as myocardial differentiation, heart tube formation, endocardial cushion development and cardiac function. We have also conducted a large-scale forward genetic screen for additional genes regulating cardiovascular development and have identified several remarkable mutants. One of these, grinch, appears to lack all myocardial cells and another, s617, appears to define a new class of cardia bifida mutants. We will focus our efforts on these two mutants, as well as 3 genes regulating endocardial cushion development and 3 other genes regulating cardiac function. Thus, we propose to continue our studies of zebrafish heart development and function with the following specific aims: 1) Investigate myocardial differentiation. We will focus our efforts on the grinch mutation which appears to block myocardial differentiation. Detailed phenotypic analysis and gene isolation will allow us to formulate more precise hypotheses regarding the role of Grinch in this process. 2) Investigate heart tube formation. These studies will focus on the s617 gene which appears to regulate heart tube formation through a previously uncharacterized mechanism. Indeed, the myocardial epithelium and the overlying pharyngeal endoderm exhibit no apparent defects in s617 mutant embryos (apart from the migration defect of the myocardium). 3) Analyze endocardial cushion development by focusing on the role of 3 genes in this process, metronome, s225 and s482. These genes appear to regulate different aspects of endocardial cushion development and our initial studies will focus on detailed phenotypic analyses and gene isolation. 4) Investigate the role of doc-oc, slip jig and daredevil in cardiac function. In order to better characterize cardiac function phenotypes, we will utilize the newly developed 'single plane illumination microscopy1 in combination with a transgenic line that allows the monitoring of intracellular calcium concentrations in vivo. 5) Continue to develop reagents and techniques to facilitate the use of the zebrafish as a rapid secondary screening system for genes regulating heart development.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Cardiovascular Differentiation and Development Study Section (CDD)
Program Officer
Schramm, Charlene A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Schools of Medicine
San Francisco
United States
Zip Code
Zhang, Qiang; Huang, Hai; Zhang, Luqing et al. (2018) Visualizing Dynamics of Cell Signaling In Vivo with a Phase Separation-Based Kinase Reporter. Mol Cell 69:334-346.e4
Schepis, Antonino; Barker, Adrian; Srinivasan, Yoga et al. (2018) Protease signaling regulates apical cell extrusion, cell contacts, and proliferation in epithelia. J Cell Biol 217:1097-1112
Reade, Anna; Motta-Mena, Laura B; Gardner, Kevin H et al. (2017) TAEL: a zebrafish-optimized optogenetic gene expression system with fine spatial and temporal control. Development 144:345-355
Pestel, Jenny; Ramadass, Radhan; Gauvrit, Sebastien et al. (2016) Real-time 3D visualization of cellular rearrangements during cardiac valve formation. Development 143:2217-27
Ahuja, Suchit; Dogra, Deepika; Stainier, Didier Y R et al. (2016) Id4 functions downstream of Bmp signaling to restrict TCF function in endocardial cells during atrioventricular valve development. Dev Biol 412:71-82
Clay, Hilary; Wilsbacher, Lisa D; Wilson, Stephen J et al. (2016) Sphingosine 1-phosphate receptor-1 in cardiomyocytes is required for normal cardiac development. Dev Biol 418:157-165
Matsuoka, Ryota L; Marass, Michele; Avdesh, Avdesh et al. (2016) Radial glia regulate vascular patterning around the developing spinal cord. Elife 5:
To, Tsz-Leung; Schepis, Antonino; Ruiz-González, Rubén et al. (2016) Rational Design of a GFP-Based Fluorogenic Caspase Reporter for Imaging Apoptosis In Vivo. Cell Chem Biol 23:875-882
Reischauer, Sven; Stone, Oliver A; Villasenor, Alethia et al. (2016) Cloche is a bHLH-PAS transcription factor that drives haemato-vascular specification. Nature 535:294-8
Orr, Nathan; Arnaout, Rima; Gula, Lorne J et al. (2016) A mutation in the atrial-specific myosin light chain gene (MYL4) causes familial atrial fibrillation. Nat Commun 7:11303

Showing the most recent 10 out of 62 publications