Understanding the mechanisms that control the formation, morphogenesis, and differentiation of mesodermal tissues such as the heart, skeletal muscles, and visceral organs is of major importance not only from a basic science point of view but also from a human health perspective. The process of mesodermal tissue development in the genetic model Drosophila has proved to be an ideal system to study these mechanisms, many of which have been strikingly conserved between invertebrates and vertebrates. Previous work in this system has shown that specific combinations of ectodermally derived signals and mesoderm-intrinsic competence factors are required to induce specific tissues in defined areas within the mesoderm. Subsequent signals from within the mesoderm help to refine these domains and generate the progenitors of individual mesodermal cell types. Our current proposal aims to dissect (in aim 1) the stage- and tissue-specific functions of a mesoderm-intrinsic regulator, tinman, which is a key mediator of signals during the induction of cardiac, dorsal somatic, and visceral muscle progenitors and, potentially, acts in cardiac patterning. We will also define (in aim 2) new mechanisms that integrate intrinsic and extrinsic inputs during mesodermal tissue induction. In particular, we aim to clarify the specific mechanism by which Wingless signals, in combination with the BMP-type of signal Dpp and tinman, induce cardiac and dorsal somatic muscle progenitors through the effector Pangolin. Further, we plan to identify and characterize an unknown repressor, which acts to prevent the induction of mesodermal genes by Dpp in the ectoderm. We will also examine how signals from the somatic mesoderm, which are mediated by Jelly Belly and its receptor Anaplastic Lymphoma Kinase, cooperate with visceral mesoderm-specific competence factors to induce visceral muscle progenitors.
In aim 3, we will define the developmental and molecular functions of the newly characterized Dorsocross T-box genes, which are induced by Dpp plus Wingless in mesodermal areas generating cardiac and dorsal somatic muscle progenitors, and later are expressed in cardiac inflow valves. Finally, in aim 4 we will utilize our detailed knowledge of the enhancers structures from genes that are induced in the dorsal mesoderm in a bioinformatics-based screen to identify novel targets of combinatorial inputs in the dorsal mesoderm. Altogether, these approaches will provide general insights into how combinations of extrinsic and intrinsic cues are integrated to elicit the exquisite developmental responses that lead to the formation and morphogenesis of distinct mesodermal tissues and organs. We anticipate that this information will continue to provide important clues to the understanding of mesodermal tissue development in vertebrates as well as the causes of human disease such as congenital heart abnormalities and organ defects. ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD030832-15
Application #
7423980
Study Section
Genetics Study Section (GEN)
Program Officer
Javois, Lorette Claire
Project Start
1994-05-01
Project End
2010-05-31
Budget Start
2008-06-01
Budget End
2010-05-31
Support Year
15
Fiscal Year
2008
Total Cost
$225,800
Indirect Cost
Name
Medical Faculty/University/Erlangen/Neuernberg
Department
Type
DUNS #
327958716
City
Erlangen
State
Country
Germany
Zip Code
91054
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
Jin, Hong; Stojnic, Robert; Adryan, Boris et al. (2013) Genome-wide screens for in vivo Tinman binding sites identify cardiac enhancers with diverse functional architectures. PLoS Genet 9:e1003195
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
Reim, Ingolf; Hollfelder, Dominik; Ismat, Afshan et al. (2012) The FGF8-related signals Pyramus and Thisbe promote pathfinding, substrate adhesion, and survival of migrating longitudinal gut muscle founder cells. Dev Biol 368:28-43
Muller, Dominik; Jagla, Teresa; Bodart, Ludivine Mihaila et al. (2010) Regulation and functions of the lms homeobox gene during development of embryonic lateral transverse muscles and direct flight muscles in Drosophila. PLoS One 5:e14323
Lo, Patrick C H; Zaffran, Stephane; Senatore, Sebastien et al. (2007) The Drosophila Hand gene is required for remodeling of the developing adult heart and midgut during metamorphosis. Dev Biol 311:287-96
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

Showing the most recent 10 out of 31 publications