Fragile X mental retardation is caused by the absence of expression of the Fragile X Mental Retardation Protein, FMRP. FMRP is an RNA binding protein found in a large, RNA-protein complex called a messenger ribonucleoprotein (mRNP) particle. FMRP is located primarily in the cytoplasm but shuttles into and out of the nucleus. All of these functions - nuclear translocation, RNA binding, and protein-protein interactions - have been shown in other systems to be modulated by phosphorylation. In preparations from rat brain, there is evidence that stimulation of the group 1 metabotropic glutamate receptors (mGluRs) increases expression of rodent FMRP (Fmrp). We propose that mGluR stimulation, which activates kinases, results in the phosphorylation the Fmrp containing-mRNP to modulate its function. We will characterize the role of phosphorylation on Fmrp function through the use of transfected cell lines, purified recombinant Fmrp and neuronal cultures in the following specific aims: 1. Examine the role of tyrosine phosphorylation on the intracellular localization, RNA binding, and protein-protein interactions of Fmrp. 2. Identify serine/threonine kinases that phosphorylate Fmrp and characterize the role of this phosphorylation on the intracellular localization, RNA binding and protein-protein interactions of Fmrp. 3. Characterize the effect of m-GluR-stimulation on the mRNP containing the FmrI mRNA. Understanding how phosphorylation affects Fmrp function, particularly in response to receptor stimulation in the brain, will give insight into the normal function of Fmrp, as well as how its absence leads to mental retardation.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD041591-02
Application #
6620740
Study Section
Special Emphasis Panel (ZRG1-MDCN-1 (01))
Program Officer
Vitkovic, Ljubisa
Project Start
2002-03-01
Project End
2003-08-15
Budget Start
2003-03-01
Budget End
2003-08-15
Support Year
2
Fiscal Year
2003
Total Cost
$80,656
Indirect Cost
Name
Emory University
Department
Genetics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Winograd, Claudia; Ceman, Stephanie (2012) Exploring the zebra finch Taeniopygia guttata as a novel animal model for the speech-language deficit of fragile X syndrome. Results Probl Cell Differ 54:181-97
Blackwell, Ernest; Zhang, Xing; Ceman, Stephanie (2010) Arginines of the RGG box regulate FMRP association with polyribosomes and mRNA. Hum Mol Genet 19:1314-23
Kim, Miri; Bellini, Michel; Ceman, Stephanie (2009) Fragile X mental retardation protein FMRP binds mRNAs in the nucleus. Mol Cell Biol 29:214-28
Cheever, Anne; Ceman, Stephanie (2009) Phosphorylation of FMRP inhibits association with Dicer. RNA 15:362-6
Cheever, Anne; Ceman, Stephanie (2009) Translation regulation of mRNAs by the fragile X family of proteins through the microRNA pathway. RNA Biol 6:175-8
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
Winograd, C; Clayton, D; Ceman, S (2008) Expression of fragile X mental retardation protein within the vocal control system of developing and adult male zebra finches. Neuroscience 157:132-42
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
Stetler, April; Winograd, Claudia; Sayegh, Joyce et al. (2006) Identification and characterization of the methyl arginines in the fragile X mental retardation protein Fmrp. Hum Mol Genet 15:87-96
Ceman, Stephanie; O'Donnell, William T; Reed, Matt et al. (2003) Phosphorylation influences the translation state of FMRP-associated polyribosomes. Hum Mol Genet 12:3295-305