The GATA-4/5/6 subfamily of transcription factors regulates various aspects of cardiogenesis, from cell specification through heart tube morphogenesis and valve formation. The hypothesis of this proposal is that the GATA-4/5/6 genes contribute to a combinatorial code that defines cellular and morphological phenotypes during multiple steps of cardiogenesis. It will be important to determine the relative contribution of each gene to cardiogenesis, and how their relative expression patterns are established by upstream regulatory programs. Innovative animal models are needed to overcome limitations to current progress. We propose to use Xenopus embryos and novel lines of transgenic zebrafish to understand the function and regulation of GATA factors during heart development. The following aims will test the specificity of function and regulatory mechanisms controlling GATA-4/5/6: 1. Define the specificity of function for GATA-4/5/6 during early cardiogenesis. The Xenopus system will be exploited to effectively inhibit expression of each gene alone or in combination, within specific germ layers of embryos, and during specific induction assays in explants. 2. Define the role of regulatory factors to establish and maintain the GATA-4 cardiogenic expression pattern. Novel lines of transgenic zebrafish were generated that express GFP under the control of GATA-4 regulatory sequences. Using a reverse genetic approach the transgenic system will be used to define the cis-elements that are required to target expression to specific domains of the normal GATA-4 pattem, and the role of T-box factors will be further investigated since T-box binding sites regulate activity of an already identified upstream enhancer. 3. Identify novel regulatory pathways that control expression of GATA-4 and GATA-6. The expression patterns for these key regulatory genes are overlapping but distinct and are likely therefore to be controlled by some common pathways, but also some that arc specific. Candidate pathways will be tested in the context of our reporter fish and a forward genetic screen will be used to identify genes that control expression of GATA-4, GATA-6, or both.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL064282-07
Application #
7058255
Study Section
Special Emphasis Panel (ZRG1-CDD (01))
Program Officer
Schramm, Charlene A
Project Start
2000-02-15
Project End
2009-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
7
Fiscal Year
2006
Total Cost
$407,689
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Sedletcaia, Anya; Evans, Todd (2011) Heart chamber size in zebrafish is regulated redundantly by duplicated tbx2 genes. Dev Dyn 240:1548-57
Kikuchi, Kazu; Holdway, Jennifer E; Werdich, Andreas A et al. (2010) Primary contribution to zebrafish heart regeneration by gata4(+) cardiomyocytes. Nature 464:601-5
Choudhuri, Avik; Evans, Todd; Maitra, Umadas (2010) Non-core subunit eIF3h of translation initiation factor eIF3 regulates zebrafish embryonic development. Dev Dyn 239:1632-44
Holtzinger, Audrey; Rosenfeld, Gabriel E; Evans, Todd (2010) Gata4 directs development of cardiac-inducing endoderm from ES cells. Dev Biol 337:63-73
Das, Bhaskar C; Mahalingam, Sakkarapalayam M; Panda, Lipsa et al. (2010) Design and Synthesis of Potential New Apoptosis Agents: Hybrid Compounds Containing Perillyl Alcohol and New Constrained Retinoids. Tetrahedron Lett 51:1462-1466
Rikin, Amir; Evans, Todd (2010) The tbx/bHLH transcription factor mga regulates gata4 and organogenesis. Dev Dyn 239:535-47
Rikin, Amir; Rosenfeld, Gabriel E; McCartin, Kellie et al. (2010) A reverse genetic approach to test functional redundancy during embryogenesis. J Vis Exp :
Das, Bhaskar C; McCartin, Kellie; Liu, Ting-Chun et al. (2010) A forward chemical screen in zebrafish identifies a retinoic acid derivative with receptor specificity. PLoS One 5:e10004
Torregroza, Ingrid; Evans, Todd; Das, Bhaskar C (2009) A forward chemical screen using zebrafish embryos with novel 2-substituted 2H-chromene derivatives. Chem Biol Drug Des 73:339-45
Das, Bhaskar C; Mahalingam, Sakkarapalayam M; Evans, Todd (2009) Design and synthesis of novel pinacolylboronate containing combretastatin 'antimitotic agent' analogues. Tetrahedron Lett 50:3031-3034

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