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, though recent studies in our laboratory and others have made significant progress. 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 its functional partner Expanded in Drosophila, particularly in relation to the control of cell proliferation by the Hippo pathway. In the next funding period, we plan to continue our studies of Merlin and Expanded function in developing organisms and in individual cells. Specifically, the proposed experiments will: 1) Elucidate functional interactions between Merlin/Expanded and the HSW pathway. Specifically we will test the hypothesis that Expanded functions downstream of Hippo to regulate the transcriptional coactivator Yorkie. 2) Understand the role of Merlin and Expanded in regulating receptor localization and availability at the plasma membrane. 3) Examine the role of signaling by the Hippo, Salvador, Warts pathway on regulating receptor abundance at the cell surface. These experiments are expected to provide insights into the functions of Merlin, Expanded and the Hippo pathway in regulating proliferation. 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.
The experiments in this proposal are designed to provide insights into the functions of Merlin (the Neurofibromatosis 2 tumor suppressor), Expanded and the Hippo pathway in regulating receptor trafficking and proliferation. In addition, the proposed experiments should lead to a better understanding of the cellular processes that establish specialized membrane domains in specialized cells such as neurons and epithelial cells. 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.
|Xu, Jiajie; Vanderzalm, Pamela J; Ludwig, Michael et al. (2018) Yorkie Functions at the Cell Cortex to Promote Myosin Activation in a Non-transcriptional Manner. Dev Cell 46:271-284.e5|
|Dickie, Erin W; Ameis, Stephanie H; Shahab, Saba et al. (2018) Personalized Intrinsic Network Topography Mapping and Functional Connectivity Deficits in Autism Spectrum Disorder. Biol Psychiatry 84:278-286|
|Di Martino, Adriana; O'Connor, David; Chen, Bosi et al. (2017) Enhancing studies of the connectome in autism using the autism brain imaging data exchange II. Sci Data 4:170010|
|Matakatsu, Hitoshi; Blair, Seth S; Fehon, Richard G (2017) Size does matter! Cell Cycle 16:907-908|
|Matakatsu, Hitoshi; Blair, Seth S; Fehon, Richard G (2017) The palmitoyltransferase Approximated promotes growth via the Hippo pathway by palmitoylation of Fat. J Cell Biol 216:265-277|
|Su, Ting; Ludwig, Michael Z; Xu, Jiajie et al. (2017) Kibra and Merlin Activate the Hippo Pathway Spatially Distinct from and Independent of Expanded. Dev Cell 40:478-490.e3|
|Zhang, Yifei; Wang, Xing; Matakatsu, Hitoshi et al. (2016) The novel SH3 domain protein Dlish/CG10933 mediates fat signaling in Drosophila by binding and regulating Dachs. Elife 5:|
|Alaerts, Kaat; Nayar, Kritika; Kelly, Clare et al. (2015) Age-related changes in intrinsic function of the superior temporal sulcus in autism spectrum disorders. Soc Cogn Affect Neurosci 10:1413-23|
|Valk, Sofie L; Di Martino, Adriana; Milham, Michael P et al. (2015) Multicenter mapping of structural network alterations in autism. Hum Brain Mapp 36:2364-73|
|Vinette, Sarah A; Bray, Signe (2015) Variation in functional connectivity along anterior-to-posterior intraparietal sulcus, and relationship with age across late childhood and adolescence. Dev Cogn Neurosci 13:32-42|
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