Neurofibromatosis type 2 (NF2), a dominantly inherited disease characterized by the formation of bilateral vestibular Schwannomas (resulting in deafness) and other tumors, is caused by loss of the tumor suppressor protein Merlin, a member of the FERM domain superfamily. Studies using the fruit fly Drosophila and subsequently confirmed in mammalian systems indicate that Merlin is an upstream component of the Hippo/Salvador/Warts (HSW) pathway, a conserved signal transduction pathway that regulates tissue growth. Mutations in Merlin and other HSW pathway components are believed to cause tumors because they cause activation of an oncogenic protein Yorkie/YAP and increased expression of growth promoting genes. 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. We seek to understand how Merlin and the other HSW components are organized into a signaling complex at the cell cortex, what controls the activity of this complex, and how feedback regulation operates within the pathway. We propose that Merlin and Kibra nucleate formation of a signaling complex at a site separate from intercellular junctions, and thus that these proteins can function in parallel to another upstream regulator, Expanded. We also plan to study how cortical tension regulates pathway activity, and in turn how pathway activity might control cortical tension. To address these questions, we have developed tools and techniques that allow us to examine the localization and dynamics of HSW pathway proteins expressed at endogenous levels in living tissues. Using with the exquisite genetic tools available in Drosophila, we can now elucidate the role of each pathway component in assembling and activating the HSW pathway. These experiments are expected to provide insights into NF2, tumor suppression in general, and the normal 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 tissue growth and determine cell fate during development and regeneration.

Public Health Relevance

Neurofibromatosis type 2 (NF2) is caused by loss of the tumor suppressor protein Merlin. Studies initiated using the fruit fly Drosophila and subsequently confirmed in mammals indicate that Merlin is part of a cellular mechanism, called the Hippo/Salvador/Warts (HSW) signaling pathway that regulates tissue growth during development. Our goal is to use the powerful genetic and cell biological tools available for Drosophila research to understand how Merlin functions to regulate the HSW pathway so that we can understand what goes wrong in the NF2 disease and ultimately develop therapies to treat NF2 patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS034783-21
Application #
9747370
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Morris, Jill A
Project Start
1996-01-01
Project End
2021-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
21
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Chicago
Department
Genetics
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
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
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
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
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

Showing the most recent 10 out of 43 publications