Cell rearrangement is responsible for more morphogenetic (shape) changes during embryogenesis than any other process, and is a key component of tumor cell metastasis. Oriented rearrangement of cells with an epithelium (cell sheet) is essential for elongation of a number of different tubular organs, such as gut and kidney. The Drosophila hindgut, homologous in many features to the vertebrate colon, is an excellent genetic model in which to study epithelial cell rearrangement. We have defined a transcriptional regulatory hierarchy that establishes the anterior domain of the hindgut, and have shown that expression in this domain of the Drosophila ligand for the JAK/STAT pathway is required for oriented cell rearrangement. Most recently, we have demonstrated that one of the Rho-family small GTPases, Rac, is required for hindgut cell rearrangement. We propose to characterize, at high resolution, cell rearrangement, particularly the protrusions between rearranging cells, in both fixed and living, wild-type and Rac mutant embryos. Our testable hypothesis is that spatially localized modulation of Rac activity via specific GEFs, and interaction of activated Rac with specific targets, is required to promote changes in cell shape and motility, and thereby mediolateral cell intercalation, in the hindgut. In the proposed analysis, we will identify and characterize these Rac-interactors in the hindgut by lossof- function genetic analysis of candidate genes, and by screening of a novel expression library for rescue of the Rac mutant hindgut phenotype. This will provide a unique, in vivo understanding of the molecular basis of oriented cell rearrangement. In the course of this work we will generate multiple genetically engineered Drosophila strains that will allow novel approaches to the analysis of organogenesis. This work, by providing insight into both cell rearrangement and tubule elongation, has important implications for both cancer therapy and tissue engineering. ? ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD009948-31
Application #
7389569
Study Section
Development - 1 Study Section (DEV)
Program Officer
Javois, Lorette Claire
Project Start
1976-09-30
Project End
2009-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
31
Fiscal Year
2008
Total Cost
$313,714
Indirect Cost
Name
University of California Los Angeles
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Milchanowski, Allison B; Henkenius, Amy L; Narayanan, Maya et al. (2004) Identification and characterization of genes involved in embryonic crystal cell formation during Drosophila hematopoiesis. Genetics 168:325-39
Patel, Parthive H; Thapar, Nitika; Guo, Lea et al. (2003) Drosophila Rheb GTPase is required for cell cycle progression and cell growth. J Cell Sci 116:3601-10
Johansen, Katherine A; Green, Ryan B; Iwaki, D David et al. (2003) The Drm-Bowl-Lin relief-of-repression hierarchy controls fore- and hindgut patterning and morphogenesis. Mech Dev 120:1139-51
Hao, Irene; Green, Ryan B; Dunaevsky, Olga et al. (2003) The odd-skipped family of zinc finger genes promotes Drosophila leg segmentation. Dev Biol 263:282-95
Johansen, Katherine A; Iwaki, D David; Lengyel, Judith A (2003) Localized JAK/STAT signaling is required for oriented cell rearrangement in a tubular epithelium. Development 130:135-45
Lengyel, Judith A; Iwaki, D David (2002) It takes guts: the Drosophila hindgut as a model system for organogenesis. Dev Biol 243:1-19
Green, Ryan B; Hatini, Victor; Johansen, Katherine A et al. (2002) Drumstick is a zinc finger protein that antagonizes Lines to control patterning and morphogenesis of the Drosophila hindgut. Development 129:3645-56
Chen, Yueh-Jung; Chiang, Chuen-Sheue; Weng, Li-Chuan et al. (2002) Tramtrack69 is required for the early repression of tailless expression. Mech Dev 116:75-83
Iwaki, D David; Lengyel, Judith A (2002) A Delta-Notch signaling border regulated by Engrailed/Invected repression specifies boundary cells in the Drosophila hindgut. Mech Dev 114:71-84
Iwaki, D D; Johansen, K A; Singer, J B et al. (2001) drumstick, bowl, and lines are required for patterning and cell rearrangement in the Drosophila embryonic hindgut. Dev Biol 240:611-26

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