Notch receptors generate different types of differentiation signals during development of humans. Accordingly, their loss or aberrant activities result in different types of developmental defects and diseases. To understand the basis for these maladies, and be able to deftly deal with each one of them, we must understand all the different signals generated by these receptors. Drosophila offers an ideal system for the purpose. During differentiation of the central nervous system and epidermis in Drosophila embryos, Notch generates four to five different types of signals. The signals generated to specify the epidermal precursor cells are well understood. However, very little is known about the other types of Notch signals, the intracellular pathways transducing them, or the mechanism by which they are generated. Recent studies show that the full-length Notch receptor, the primary receptor, generates two secondary receptors showing different activities than the primary receptor. The different activities of the three receptors together have the potential to account for all the different types of differentiation signals generated by Notch. The proposed studies will use molecular genetic and biochemical analyses to determine the following. (1) The nature of in vivo signals generated by the different Notch receptors at different stages of differentiation. (2) Whether or not signals from the secondary receptors are transduced by the same pathway that transduces the epidermal precursor cell signals. (3) Whether proteins known to bind Notch regulate the production and activities of the different receptors. These studies are expected to lead to an understanding of how the primary and secondary Notch receptors regulate differentiation of tissues during development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS043122-04S2
Application #
7100000
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Owens, David F
Project Start
2001-07-01
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2006-06-30
Support Year
4
Fiscal Year
2005
Total Cost
$30,000
Indirect Cost
Name
University of Vermont & St Agric College
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
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Shepherd, Andrew K; Singh, Ravinder; Wesley, Cedric S (2009) Notch mRNA expression in Drosophila embryos is negatively regulated at the level of mRNA 3' processing. PLoS One 4:e8063
LeComte, Matthew; Wesley, Umadevi V; Mok, Lee-Peng et al. (2006) Evidence for the involvement of dominant-negative Notch molecules in the normal course of Drosophila development. Dev Dyn 235:411-26
Mok, Lee-Peng; Qin, Tielin; Bardot, Boris et al. (2005) Delta activity independent of its activity as a ligand of Notch. BMC Dev Biol 5:6
Bardot, Boris; Mok, Lee-Peng; Thayer, Tristan et al. (2005) The Notch amino terminus regulates protein levels and Delta-induced clustering of Drosophila Notch receptors. Exp Cell Res 304:202-23
Ahimou, Francois; Mok, Lee-Peng; Bardot, Boris et al. (2004) The adhesion force of Notch with Delta and the rate of Notch signaling. J Cell Biol 167:1217-29
Wesley, Cedric S; Mok, Lee-Peng (2003) Regulation of Notch signaling by a novel mechanism involving suppressor of hairless stability and carboxyl terminus-truncated notch. Mol Cell Biol 23:5581-93