reproduced verbatim): The long term goals are to understand how steroid hormones regulate diverse patterns of development within the CNS. Studies on the insect models, Drosophila melonogaster and Manduca sexta, have shown that ecdysteroids can activate two discrete developmental programs depending on steroid concentration. Low steroid levels control tissue patterning and cellular determination while high steroid concentrations promote cell maturation. Ecdysteropid action is mediated through the ecdysone receptor (EcR) and its heterodimer partner ultraspiracle (USP). A mosaic analysis of clonal tissues that lacks USP suggests that the transcriptional silencing and transcriptional activation functions of the EcR/USP complex have different developmental functions; the former primarily mediating programs of tissue patterning and cell determination while the latter is involved in programs of cellular maturation. Insights gained about how these silencing and activational functions of the EcR/USP complex relate to developmental programs in these insect models will also be directly applicable to understanding homologous signaling systems in vertebrates -- those mediating the actions of thyroid hormone and the retinoids.
Specific aims are: 1) determine the receptors and signaling molecules that cause the pre-metamorphic changes in Drosophila. 2) Use a mosaic analysis to determine the role of the ligand binding and DNA binding domains of EcR in mediating the two programs of developmental response. 3) Use the mosaic analysis of EcR mutants and the misexpression of EcR isoforms to examine the ability of each isoform to support patterning and determination processes versus maturational processes. 4) Use USP clones and in vitro challenges with ecdysteroids to examine how cell determination and cell maturation programs interact during development. 5) Utilize a neuron-myoblast coculture system to examine how neurons are able to direct the type of EcR isoform expressed in embryonic muscle and how receptor isoform choice relates to muscle growth and maturation responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS029971-10
Application #
6330453
Study Section
Special Emphasis Panel (ZRG1-MDCN-6 (01))
Program Officer
Finkelstein, Robert
Project Start
1991-09-30
Project End
2003-11-30
Budget Start
2000-12-01
Budget End
2001-11-30
Support Year
10
Fiscal Year
2001
Total Cost
$306,896
Indirect Cost
Name
University of Washington
Department
Zoology
Type
Schools of Arts and Sciences
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Brown, Heather L D; Truman, James W (2009) Fine-tuning of secondary arbor development: the effects of the ecdysone receptor on the adult neuronal lineages of the Drosophila thoracic CNS. Development 136:3247-56
Brown, Heather L D; Cherbas, Lucy; Cherbas, Peter et al. (2006) Use of time-lapse imaging and dominant negative receptors to dissect the steroid receptor control of neuronal remodeling in Drosophila. Development 133:275-85
Williams, Darren W; Kondo, Shu; Krzyzanowska, Agnieszka et al. (2006) Local caspase activity directs engulfment of dendrites during pruning. Nat Neurosci 9:1234-6
MacWhinnie, Steven G B; Allee, J Paul; Nelson, Charles A et al. (2005) The role of nutrition in creation of the eye imaginal disc and initiation of metamorphosis in Manduca sexta. Dev Biol 285:285-97
Schubiger, Margrit; Carre, Clement; Antoniewski, Christophe et al. (2005) Ligand-dependent de-repression via EcR/USP acts as a gate to coordinate the differentiation of sensory neurons in the Drosophila wing. Development 132:5239-48
Zhou, Xiaofeng; Zhou, Baohua; Truman, James W et al. (2004) Overexpression of broad: a new insight into its role in the Drosophila prothoracic gland cells. J Exp Biol 207:1151-61
Schubiger, Margrit; Tomita, Shuichiro; Sung, Carl et al. (2003) Isoform specific control of gene activity in vivo by the Drosophila ecdysone receptor. Mech Dev 120:909-18
Stilwell, Geoffrey E; Nelson, Charles A; Weller, John et al. (2003) E74 exhibits stage-specific hormonal regulation in the epidermis of the tobacco hornworm, manduca sexta. Dev Biol 258:76-90
Grueber, Wesley B; Jan, Lily Y; Jan, Yuh Nung (2002) Tiling of the Drosophila epidermis by multidendritic sensory neurons. Development 129:2867-78
Riddiford, L M; Cherbas, P; Truman, J W (2000) Ecdysone receptors and their biological actions. Vitam Horm 60:Jan-73

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