During embryogenesis, cells become specified to assume a particular developmental fate according to their position in the embryo and as a result of interactions with their neighboring cells. These processes are controlled by genetic programs that involve differential expression of regulatory genes in a precisely controlled temporal and spatial pattern. One group of embryonic cells, the mesoderm, invaginates into the interior of the embryo during gastrulation, and subsequently develops into a complex pattern of different muscle types, the heart, and other tissues. The overall objective of the proposed research is to study the mechanisms that lead to the specification of individual cell identities in this germ layer. In the fruit fly Drosophila, these mechanisms can be analyzed with a powerful combination of genetic, molecular and biochemical methods. Three previously identified homeo box genes, tinman (tin), bagpipe (bap) and S59 will be used as paradigms to study the regulation of mesoderm and muscle development. Our genetic analysis suggests that tin and bap are the key genes that specify dorsal mesodermal cells to develop into gut musculature and the heart. Thus, the fundamental subdivision of the mesoderm into a dorsal (visceral) and ventral (somatic) primordium is ultimately a result of the restriction of tin and bap expression to the dorsal cells of the mesoderm. One focus of our research will therefore be to analyze the mechanisms involved in the spatial regulation of these genes. Genetic experiments will be used to examine whether inductive signals from the epidermis influence the spatial expression of tin and bap. The cis-regulatory sequences required for tin and bap regulation will be determined in transgenic flies, and biochemical experiments will be performed to characterize trans-acting factors. To obtain insight into the functions of tin and bap, the interaction with potential downstream genes will be examined. The S59 expression pattern suggests a function of this gene to specify the identity of particular body wall muscles, and this will be tested through the identification and analysis of S59 mutants. Because of the growing evidence that many regulatory mechanisms in development are conserved during evolution, the results of this research are expected to allow a better understanding of mesoderm, muscle and heart formation also in vertebrates and humans.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD030832-05
Application #
2673730
Study Section
Genetics Study Section (GEN)
Project Start
1994-05-01
Project End
1999-04-30
Budget Start
1998-05-01
Budget End
1999-04-30
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Biochemistry
Type
Schools of Medicine
DUNS #
114400633
City
New York
State
NY
Country
United States
Zip Code
10029
Frasch, Manfred (2016) Genome-Wide Approaches to Drosophila Heart Development. J Cardiovasc Dev Dis 3:
Schaub, Christoph; Frasch, Manfred (2013) Org-1 is required for the diversification of circular visceral muscle founder cells and normal midgut morphogenesis. Dev Biol 376:245-59
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Schaub, Christoph; Nagaso, Hideyuki; Jin, Hong et al. (2012) Org-1, the Drosophila ortholog of Tbx1, is a direct activator of known identity genes during muscle specification. Development 139:1001-12
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Zaffran, Stephane; Reim, Ingolf; Qian, Li et al. (2006) Cardioblast-intrinsic Tinman activity controls proper diversification and differentiation of myocardial cells in Drosophila. Development 133:4073-83
Nguyen, Hanh T; Frasch, Manfred (2006) MicroRNAs in muscle differentiation: lessons from Drosophila and beyond. Curr Opin Genet Dev 16:533-9
Wang, Jianbo; Tao, Ye; Reim, Ingolf et al. (2005) Expression, regulation, and requirement of the toll transmembrane protein during dorsal vessel formation in Drosophila melanogaster. Mol Cell Biol 25:4200-10

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