The early morphogenetic mechanisms involved in heart formation are evolutionarily conserved. To identify novel cardiogenic genes, we performed a large-scale genetic screen in Drosophila. We discovered a unique cardiac defect, called broken hearted (bro), in which pericardial cells and cardioblasts dissociate, causing loss of cardiac function and embryonic lethality. This phenotype resulted from mutations in genes encoding HMG-CoA reductase and its downstream enzymes in the mevalonate pathway, as well as G protein G31, which is geranylgeranylated, thus representing an end point of isoprenoid biosynthesis. Identification of the essential role of C in cardiac morphogenesis opened a door to discovery of the entire G protein genetic pathway required for cardiac morphogenesis. Here, we will investigate the functional mechanism of G31, and identify the G1 and G2 partners that form the cardiac heterotrimeric G protein complex with G31. From our screen, we also identified two G-protein coupled receptors (GPCRs) involved in this process. We will investigate the roles of these GPCRs using cardiac cell type specific rescue system established in our preliminary studies. Our screen also identified two bro mutations disrupting genes encoding septate junction components, indicating that septate junction formation is involved in cardiac morphogenesis. We will characterize the cell-cell junctions of Drosophila heart using electron microscopy and study the role of septate junction proteins during heart development. We will also examine how the G protein signaling mutants affect septate junction formation in the heart. These studies will fill a significant gap in the research field of heart development, and promote our understanding of the molecular mechanism of congenital heart disease. Narrative: Heart development is controlled by evolutionarily conserved genetic network. To identify genes in this network, we performed a large-scale genetic screen in Drosophila and identified a group of highly conserved genes required for heart formation. Studies of these genes promote our understanding of heart development and mechanism of congenital heart disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiovascular Differentiation and Development Study Section (CDD)
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Schramm, Charlene A
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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Zhu, Jun-Yi; Fu, Yulong; Richman, Adam et al. (2017) Validating Candidate Congenital Heart Disease Genes in Drosophila. Bio Protoc 7:
Zhu, Jun-Yi; Heidersbach, Amy; Kathiriya, Irfan S et al. (2017) The E3 ubiquitin ligase Nedd4/Nedd4L is directly regulated by microRNA 1. Development 144:866-875
Zhu, Shasha; Han, Zhe; Luo, Yan et al. (2017) Molecular mechanisms of heart failure: insights from Drosophila. Heart Fail Rev 22:91-98
Zhu, Jun-Yi; Fu, Yulong; Nettleton, Margaret et al. (2017) High throughput in vivo functional validation of candidate congenital heart disease genes in Drosophila. Elife 6:
Jiang, Z; Li, F; Wan, Y et al. (2016) LASS5 Interacts with SDHB and Synergistically Represses p53 and p21 Activity. Curr Mol Med 16:582-90
Fulga, Tudor A; McNeill, Elizabeth M; Binari, Richard et al. (2015) A transgenic resource for conditional competitive inhibition of conserved Drosophila microRNAs. Nat Commun 6:7279
Gee, Heon Yung; Zhang, Fujian; Ashraf, Shazia et al. (2015) KANK deficiency leads to podocyte dysfunction and nephrotic syndrome. J Clin Invest 125:2375-84
Zhang, Fujian; Zhao, Ying; Chao, Yufang et al. (2013) Cubilin and amnionless mediate protein reabsorption in Drosophila nephrocytes. J Am Soc Nephrol 24:209-16
Zhang, Fujian; Zhao, Ying; Han, Zhe (2013) An in vivo functional analysis system for renal gene discovery in Drosophila pericardial nephrocytes. J Am Soc Nephrol 24:191-7
Ashraf, Shazia; Gee, Heon Yung; Woerner, Stephanie et al. (2013) ADCK4 mutations promote steroid-resistant nephrotic syndrome through CoQ10 biosynthesis disruption. J Clin Invest 123:5179-89

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