Tube formation is a nearly ubiquitous process required in metazoans to construct the thoroughfares through which the various liquids and gases that sustain life flow. We focus on tube formation in the model system of the Drosophila embryonic trachea, a genetically tractable model for learning the molecules and mechanisms underlying the organization of cells into tubular organs. This application focuses on events downstream of a key transcription factor gene required for normal tube formation: trachealess (trh), which encodes a bHLH-PAS transcription factor. Trh functions as a major regulator of tube formation, not only in the trachea but also in two other tube-forming organs. In trh mutants, the primordia for these tissues remain on the embryo surface at their site of origin, failing to undergo any of the movements of tube morphogenesis. With the recent advances we have made in live imaging of tracheal morphogenesis, the identification of several early expressed Trh target genes and the discovery that two of the Trh target genes play novel roles in tube size control, we are thus poised to carry our analysis to the next level;linking molecular changes in target genes to the cell biological events of tube morphogenesis. In this proposal, we have three specific aims: (1) We unravel the roles of new Trh target genes that are expressed early and encode molecules with domain structures that suggest a role in mediating tube invagination. (2) We explore the mechanisms whereby Sano and the PCP regulators control tube size through effects on cell shape. (3) We link the molecular activity of an unusual enzyme encoded by mipp1 to tube size control and migration. For these studies, we use the collective experience of the lab to take advantage of all the tools Drosophila has to offer, including a well annotated genome, methodologies for cleanly eliminating gene function either in the whole animal or in a subset of cells, mechanisms to express both untagged and tagged versions of a given protein in any tissue, as well as methods for imaging both fixed and living tissues. We expect these studies to implicate new molecules and reveal novel mechanisms for several aspects of tube formation.

Public Health Relevance

It is clear that many of the molecules and mechanisms that occur in formation of the Drosophila trachea are shared in the formation of tubular organs in vertebrates. For example, the vertebrate neural tube, lung and liver form through the same apical constriction mechanisms required to internalize the tracheal primordia. Similarly, signaling pathways controlling tube size and migration are likely to be conserved. Thus, what we discover in the Drosophila trachea will be relevant to birth defects and common human diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE012873-13
Application #
8435295
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Burgoon, Penny W
Project Start
1999-02-01
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
13
Fiscal Year
2013
Total Cost
$445,714
Indirect Cost
$173,937
Name
Johns Hopkins University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Ismat, Afshan; Cheshire, Alan M; Andrew, Deborah J (2013) The secreted AdamTS-A metalloprotease is required for collective cell migration. Development 140:1981-93
Maruyama, Rika; Andrew, Deborah J (2012) Drosophila as a model for epithelial tube formation. Dev Dyn 241:119-35
Chung, SeYeon; Chavez, Cy; Andrew, Deborah J (2011) Trachealess (Trh) regulates all tracheal genes during Drosophila embryogenesis. Dev Biol 360:160-72
Andrew, Deborah J; Ewald, Andrew J (2010) Morphogenesis of epithelial tubes: Insights into tube formation, elongation, and elaboration. Dev Biol 341:34-55
Kerman, Bilal E; Andrew, Deborah J (2010) Staying alive: dalmation mediated blocking of apoptosis is essential for tissue maintenance. Dev Dyn 239:1609-21
Andrew, Deborah J; Baker, Bruce S (2008) Expression of the Drosophila secreted cuticle protein 73 (dsc73) requires Shavenbaby. Dev Dyn 237:1198-206
Cheshire, Alan M; Kerman, Bilal E; Zipfel, Warren R et al. (2008) Kinetic and mechanical analysis of live tube morphogenesis. Dev Dyn 237:2874-88
Kerman, Bilal E; Cheshire, Alan M; Myat, Monn Monn et al. (2008) Ribbon modulates apical membrane during tube elongation through Crumbs and Moesin. Dev Biol 320:278-88
Kerman, Bilal E; Cheshire, Alan M; Andrew, Deborah J (2006) From fate to function: the Drosophila trachea and salivary gland as models for tubulogenesis. Differentiation 74:326-48
Myat, Monn Monn; Lightfoot, Harrell; Wang, Ping et al. (2005) A molecular link between FGF and Dpp signaling in branch-specific migration of the Drosophila trachea. Dev Biol 281:38-52

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