Elucidating the mechanistic function of Fragile X Mental Retardation Protein (FMRP) in neurons is a critical goal in understanding the basis of Fragile X Syndrome. This proposal will test the hypothesis that FMRP is required for the glutamatergic regulation of mRNA transport in dendrites and its subsynaptic translation. Recent identification of mRNAs that are bound by FMRP now makes it possible to investigate whether these RNA-protein interactions occur in dendrites and at synapses. An inherent difficulty in studying RNA-protein interactions in dendrites has been the lack of suitable high resolution microscopic technology to visualize mRNA transport and identify sites of local translation. A new view of FMRP function is made possible by utilizing novel microscopic and imaging technology to visualize mRNP complexes in live neurons. We have recently shown that FMRP is localized in the form of RNA granules that exhibit dynamic and activity-dependent movements in dendrites and spines. Experiments in Specific Aim 1 will apply high resolution fluorescence in situ hybridization methods and quantitative digital imaging analysis to determine whether specific mRNAs have altered localization and regulation in hippocampal cultures from Fmr1 knockout mice. We will determine whether FMRP binding elements function as zipcodes to localize FMRP target mRNAs using transfection of reporter constructs. Experiments in Specific Aim 2 will use live cell imaging technology to determine whether glutamatergic signaling and synaptic activity regulates the dynamic trafficking of FMRP and bound mRNAs in dendrites and spines. Experiments in Specific Aim 3 will use combined imaging and biochemical methods to elucidate a role for FMRP in the glutamatergic regulation of dendritic and synaptic protein synthesis. These studies will provide new insight into the molecular and cellular basis for altered synaptic plasticity in Fragile X Syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
7R01NS051127-02
Application #
6990512
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Riddle, Robert D
Project Start
2004-12-15
Project End
2008-11-30
Budget Start
2005-12-01
Budget End
2006-11-30
Support Year
2
Fiscal Year
2006
Total Cost
$310,948
Indirect Cost
Name
Emory University
Department
Neurology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Xing, Lei; Bassell, Gary J (2013) mRNA localization: an orchestration of assembly, traffic and synthesis. Traffic 14:2-14
Nalavadi, Vijayalaxmi C; Muddashetty, Ravi S; Gross, Christina et al. (2012) Dephosphorylation-induced ubiquitination and degradation of FMRP in dendrites: a role in immediate early mGluR-stimulated translation. J Neurosci 32:2582-7
Dictenberg, Jason B; Swanger, Sharon A; Antar, Laura N et al. (2008) A direct role for FMRP in activity-dependent dendritic mRNA transport links filopodial-spine morphogenesis to fragile X syndrome. Dev Cell 14:926-39
Narayanan, Usha; Nalavadi, Vijayalaxmi; Nakamoto, Mika et al. (2008) S6K1 phosphorylates and regulates fragile X mental retardation protein (FMRP) with the neuronal protein synthesis-dependent mammalian target of rapamycin (mTOR) signaling cascade. J Biol Chem 283:18478-82
Bassell, Gary J; Warren, Stephen T (2008) Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function. Neuron 60:201-14
Wang, Houping; Dictenberg, Jason B; Ku, Li et al. (2008) Dynamic association of the fragile X mental retardation protein as a messenger ribonucleoprotein between microtubules and polyribosomes. Mol Biol Cell 19:105-14
Narayanan, Usha; Nalavadi, Vijayalaxmi; Nakamoto, Mika et al. (2007) FMRP phosphorylation reveals an immediate-early signaling pathway triggered by group I mGluR and mediated by PP2A. J Neurosci 27:14349-57
Nakamoto, Mika; Nalavadi, Vijayalaxmi; Epstein, Michael P et al. (2007) Fragile X mental retardation protein deficiency leads to excessive mGluR5-dependent internalization of AMPA receptors. Proc Natl Acad Sci U S A 104:15537-42
Antar, Laura N; Li, Chanxia; Zhang, Honglai et al. (2006) Local functions for FMRP in axon growth cone motility and activity-dependent regulation of filopodia and spine synapses. Mol Cell Neurosci 32:37-48
Grooms, Sonja Y; Noh, Kyung-Min; Regis, Roodland et al. (2006) Activity bidirectionally regulates AMPA receptor mRNA abundance in dendrites of hippocampal neurons. J Neurosci 26:8339-51

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