Neurofibromatosis type 2 (NF2), a dominantly inherited disease, is caused by mutations in Merlin (Schwannomin), a member of the Protein 4.1 superfamily. Symptoms of NF2, which usually appear by early adult life, are caused by the formation of bilateral vestibular Schwannomas (resulting in deafness) and other benign tumors. The cellular functions of Merlin and its role in tumor suppression are still largely unknown. Identifying specific proteins and signal transduction pathways with which Merlin interacts is especially important because these partners may act as genetic modifiers of NF2 disease phenotypes and provide potential targets for therapeutic agents. The common fruit fly, Drosophila, has proven to be a useful model system for understanding gene function in the context of a developing organism. The overall goal of this proposal is therefore to examine the cellular functions of Merlin and the closely related ERM protein Moesin in Drosophila, particularly in relation to the control of cell proliferation, cell polarity, and the regulation of epithelial identity. In the next funding period, we plan to continue our studies of Merlin function in developing organisms and in individual cells. Specifically, the proposed experiments will: 1) Examine the mechanisms by which Merlin regulates cell proliferation. Specifically, we will test the hypothesis that Merlin functions to negatively regulate the EGF receptor pathway. 2) Examine the mechanism by which the closely related ERM proteins function to regulate Rho pathway activity, and how this relates to apical/basal polarity and epithelial integrity. 3) Explore the functional relationship between Merlin and the ERM proteins, testing for synergistic or antagonistic interactions between them. These experiments are expected to provide insights into the functions of Merlin and the ERM proteins. Thus they will contribute to our understanding of human NF2, tumor suppression in general, and carcinogenesis. In addition, the proposed experiments should lead to a better understanding of the cellular processes that establish specialized membrane domains in epithelial cells and neurons. Finally, these studies should contribute to work on the mechanisms by which cellular interactions function to control cell growth and determine cell fate during development

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS034783-12
Application #
7173287
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Fountain, Jane W
Project Start
1996-01-01
Project End
2008-12-31
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
12
Fiscal Year
2007
Total Cost
$300,799
Indirect Cost
Name
University of Chicago
Department
Genetics
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
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