Abstract

The investigator's hypothesis is that there are separable genetic pathways which configure the ventricle of the early embryonic heart. Their goal is to identify the genes essential to this patterning and to understand their cellular and embryological mechanisms of action. They focus upon four mutations we discovered which perturb formation of the ventricle in embryonic zebrafish: bs2lb, lonely atrium, and Pandora , mutants lack the ventricle, while the atrium is relatively preserved; heart and soul mutant embryos have ventricular tissue contained within the atrium of the early heart tube.
In Specific Aim 1, they propose to examine the hypothesis that these mutations perturb preventricular cells in the embryonic heart field, by examination of cell lineage and patterns of expression of myocardial genes in wild-type and mutant fish.
In Specific Aim 2, they propose to clone the four mutations by positional strategies. They believe that these genes provide important insights. First; they provide the necessary linchpins to begin molecular dissection of the steps which configure the ventricle. Second, they speak to an evolutionary issue, because the ventricle is a vertebrate-specific addition along the chordate lineage. Third, these genes may have relevance to congenital disorders, such as hypoplastic heart syndromes, and to potential therapeutic replenishment of contractile myocardium of the failing heart.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063206-04
Application #
6527196
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Pearson, Gail D
Project Start
1999-09-01
Project End
2003-07-31
Budget Start
2002-08-01
Budget End
2003-07-31
Support Year
4
Fiscal Year
2002
Total Cost
$428,169
Indirect Cost

  Institution

Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199

  Publications

Meder, Benjamin; Katus, Hugo A; Rottbauer, Wolfgang (2008) Right into the heart of microRNA-133a. Genes Dev 22:3227-31
Bendig, Garnet; Grimmler, Matthias; Huttner, Inken G et al. (2006) Integrin-linked kinase, a novel component of the cardiac mechanical stretch sensor, controls contractility in the zebrafish heart. Genes Dev 20:2361-72
Rottbauer, Wolfgang; Wessels, Georgia; Dahme, Tillman et al. (2006) Cardiac myosin light chain-2: a novel essential component of thick-myofilament assembly and contractility of the heart. Circ Res 99:323-31
Mably, John D; Chuang, Lesley P; Serluca, Fabrizio C et al. (2006) santa and valentine pattern concentric growth of cardiac myocardium in the zebrafish. Development 133:3139-46
Rottbauer, Wolfgang; Just, Steffen; Wessels, Georgia et al. (2005) VEGF-PLCgamma1 pathway controls cardiac contractility in the embryonic heart. Genes Dev 19:1624-34
Ebert, A M; Hume, G L; Warren, K S et al. (2005) Calcium extrusion is critical for cardiac morphogenesis and rhythm in embryonic zebrafish hearts. Proc Natl Acad Sci U S A 102:17705-10
Mably, John D; Mohideen, Manzoor Ali P K; Burns, C Geoffrey et al. (2003) heart of glass regulates the concentric growth of the heart in zebrafish. Curr Biol 13:2138-47
Mayer, Alan N; Fishman, Mark C (2003) Nil per os encodes a conserved RNA recognition motif protein required for morphogenesis and cytodifferentiation of digestive organs in zebrafish. Development 130:3917-28
Childs, Sarah; Chen, Jau-Nian; Garrity, Deborah M et al. (2002) Patterning of angiogenesis in the zebrafish embryo. Development 129:973-82
Garrity, Deborah M; Childs, Sarah; Fishman, Mark C (2002) The heartstrings mutation in zebrafish causes heart/fin Tbx5 deficiency syndrome. Development 129:4635-45

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