Abstract
Fragile X syndrome (FXS) results from the loss of the fragile X mental retardation protein (FMRP), an RNA-binding protein that regulates a variety of cytoplasmic mRNAs. FMRP regulates mRNA translation and may be important in mRNA localization to dendrites. We report a third cytoplasmic regulatory function for FMRP: control of mRNA stability. In mice, we found that FMRP binds, in vivo, the mRNA encoding PSD-95, a key molecule that regulates neuronal synaptic signaling and learning. This interaction occurs through the 3' untranslated region of the PSD-95 (also known as Dlg4) mRNA, increasing message stability. Moreover, stabilization is further increased by mGluR activation. Although we also found that the PSD-95 mRNA is synaptically localized in vivo, localization occurs independently of FMRP. Through our functional analysis of this FMRP target we provide evidence that dysregulation of mRNA stability may contribute to the cognitive impairments in individuals with FXS.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Brain / cytology
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Cell Survival / physiology
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Cells, Cultured
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Disks Large Homolog 4 Protein
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Electrophoretic Mobility Shift Assay / methods
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Embryo, Mammalian
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Fragile X Mental Retardation Protein / genetics
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Fragile X Mental Retardation Protein / physiology*
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Guanylate Kinases
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Immunoprecipitation / methods
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In Situ Hybridization / methods
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Intracellular Signaling Peptides and Proteins / genetics*
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Intracellular Signaling Peptides and Proteins / metabolism
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Male
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Membrane Proteins / genetics*
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Membrane Proteins / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Neurons / metabolism
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Protein Biosynthesis
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RNA Stability / physiology*
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RNA, Messenger / metabolism*
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Reverse Transcriptase Polymerase Chain Reaction / methods
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Transfection
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Tubulin / metabolism
Substances
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Disks Large Homolog 4 Protein
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Dlg4 protein, mouse
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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RNA, Messenger
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Tubulin
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Fragile X Mental Retardation Protein
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Guanylate Kinases