The fragile X mental retardation protein is required for type-I metabotropic glutamate receptor-dependent translation of PSD-95

Fragile X syndrome (FXS) is a common inherited cause of mental retardation resulting from the absence of the fragile X mental retardation protein (FMRP). FMRP is thought to regulate the translation of target mRNAs, including its own transcript. Here we show that the levels of FMRP are rapidly up-regulated in primary cortical neurons in response to the type-I metabotropic glutamate receptor (mGluR) agonist S-3,5-dihydrophenylglycine. These changes require new protein synthesis but not transcription and are specific to mGluR activation. We also demonstrate that the mRNA for PSD-95, a scaffolding protein involved in synaptic plasticity, contains a highly conserved canonical binding site for FMRP within its 3′ UTR. Furthermore, PSD-95 is rapidly translated in response to S-3,5-dihydrophenylglycine. Finally, we show that these mGluR-dependent changes in PSD-95 expression are lost in neurons derived from FMRP knockout mice, a model of FXS. Taken together, these studies suggest that FMRP is required for mGluR-dependent translation of PSD-95 and provide insights into the pathophysiology of FXS.

[1]  I. Weiler,et al.  Abnormal dendritic spines in fragile X knockout mice: maturation and pruning deficits. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[2]  S. Ceman,et al.  Isolation of an FMRP-Associated Messenger Ribonucleoprotein Particle and Identification of Nucleolin and the Fragile X-Related Proteins as Components of the Complex , 1999, Molecular and Cellular Biology.

[3]  M. Bear,et al.  Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression. , 2000, Science.

[4]  S. Hersch,et al.  Fragile X Mental Retardation Protein: Nucleocytoplasmic Shuttling and Association with Somatodendritic Ribosomes , 1997, The Journal of Neuroscience.

[5]  C. Gunter,et al.  Purified Recombinant Fmrp Exhibits Selective RNA Binding as an Intrinsic Property of the Fragile X Mental Retardation Protein* , 1998, The Journal of Biological Chemistry.

[6]  R. Nicoll,et al.  PSD-95 involvement in maturation of excitatory synapses. , 2000, Science.

[7]  W. Abraham,et al.  Metabotropic Glutamate Receptors Trigger Homosynaptic Protein Synthesis to Prolong Long-Term Potentiation , 2000, The Journal of Neuroscience.

[8]  É. Khandjian,et al.  The fragile X mental retardation protein is associated with poly(A)+ mRNA in actively translating polyribosomes. , 1997, Human molecular genetics.

[9]  K. Kalil,et al.  Reorganization and Movement of Microtubules in Axonal Growth Cones and Developing Interstitial Branches , 1999, The Journal of Neuroscience.

[10]  H. Okado,et al.  Continual remodeling of postsynaptic density and its regulation by synaptic activity , 1999, Nature Neuroscience.

[11]  Gerald M. Rubin,et al.  Drosophila Fragile X-Related Gene Regulates the MAP1B Homolog Futsch to Control Synaptic Structure and Function , 2001, Cell.

[12]  P. Jin,et al.  Understanding the molecular basis of fragile X syndrome. , 2000, Human molecular genetics.

[13]  I. Weiler,et al.  Synaptic regulation of protein synthesis and the fragile X protein , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[14]  I. Weiler,et al.  Fragile X mental retardation protein is translated near synapses in response to neurotransmitter activation. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[15]  J. Darnell,et al.  Microarray Identification of FMRP-Associated Brain mRNAs and Altered mRNA Translational Profiles in Fragile X Syndrome , 2001, Cell.

[16]  Lili Wan,et al.  Characterization of dFMR1, a Drosophila melanogaster Homolog of the Fragile X Mental Retardation Protein , 2000, Molecular and Cellular Biology.

[17]  A. Ostareck-Lederer,et al.  Evidence that fragile X mental retardation protein is a negative regulator of translation. , 2001, Human molecular genetics.

[18]  Atsuko Fukunaga,et al.  A novel class of antagonists for metabotropic glutamate receptors, 7-(Hydroxyimino)cyclopropa[b]chromen-1a-carboxylates , 1996 .

[19]  I. Weiler,et al.  Calcium Ion Impedes Translation Initiation at the Synapse , 1996, Journal of neurochemistry.

[20]  Ben A. Oostra,et al.  Screening and Diagnosis for the Fragile X Syndrome among the Mentally Retarded: An Epidemiological and Psychological Survey , 1997 .

[21]  J. Malter,et al.  Whisker stimulation-dependent translation of FMRP in the barrel cortex requires activation of type I metabotropic glutamate receptors. , 2003, Brain research. Molecular brain research.

[22]  D. Bredt,et al.  Synaptic Targeting of the Postsynaptic Density Protein PSD-95 Mediated by Lipid and Protein Motifs , 1999, Neuron.

[23]  T. Webb,et al.  Prevalence of fragile X syndrome. , 1996, Journal of medical genetics.

[24]  Mark F. Bear,et al.  Altered synaptic plasticity in a mouse model of fragile X mental retardation , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[25]  H. Bading,et al.  Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways , 2002, Nature Neuroscience.

[26]  M. Ito,et al.  Induction of long-term depression in cerebellar Purkinje cells requires a rapidly turned over protein. , 2001, Journal of neurophysiology.

[27]  C. Ehresmann,et al.  The fragile X mental retardation protein binds specifically to its mRNA via a purine quartet motif , 2001, The EMBO journal.

[28]  P. Bergold,et al.  Requirement of protein synthesis for group I mGluR-mediated induction of epileptiform discharges. , 1998, Journal of neurophysiology.

[29]  E. Eichler,et al.  Human and murine FMR-1: alternative splicing and translational initiation downstream of the CGG–repeat , 1993, Nature Genetics.

[30]  I. Weiler,et al.  Metabotropic glutamate receptors trigger postsynaptic protein synthesis. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Neal Sweeney,et al.  Synaptic Strength Regulated by Palmitate Cycling on PSD-95 , 2002, Cell.

[32]  D. Bredt,et al.  Synaptic Targeting of the Postsynaptic Density Protein PSD-95 Mediated by a Tyrosine-based Trafficking Signal* , 2000, The Journal of Biological Chemistry.

[33]  J. Darnell,et al.  Fragile X Mental Retardation Protein Targets G Quartet mRNAs Important for Neuronal Function , 2001, Cell.

[34]  I. Weiler,et al.  Abnormal dendritic spine characteristics in the temporal and visual cortices of patients with fragile-X syndrome: a quantitative examination. , 2001, American journal of medical genetics.

[35]  Mark F. Bear,et al.  Internalization of ionotropic glutamate receptors in response to mGluR activation , 2001, Nature Neuroscience.

[36]  M. Sheng,et al.  Heterogeneity in the Molecular Composition of Excitatory Postsynaptic Sites during Development of Hippocampal Neurons in Culture , 1998, The Journal of Neuroscience.

[37]  S. Warren,et al.  The fragile X mental retardation protein inhibits translation via interacting with mRNA. , 2001, Nucleic acids research.

[38]  J. Eberwine,et al.  Identification of sites for exponential translation in living dendrites , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[39]  R. Morris,et al.  Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein , 1998, Nature.

[40]  R. Haworth,et al.  Stimulation of Na-K-2Cl cotransporter in neurons by activation of Non-NMDA ionotropic receptor and group-I mGluRs. , 2001, Journal of neurophysiology.

[41]  H. Okado,et al.  Spine Formation and Correlated Assembly of Presynaptic and Postsynaptic Molecules , 2001, The Journal of Neuroscience.

[42]  Dane M. Chetkovich,et al.  Dual Palmitoylation of Psd-95 Mediates Its Vesiculotubular Sorting, Postsynaptic Targeting, and Ion Channel Clustering , 2000, The Journal of cell biology.

[43]  D. Absher,et al.  FMRP associates with polyribosomes as an mRNP, and the I304N mutation of severe fragile X syndrome abolishes this association. , 1997, Molecular cell.

[44]  Roger A. Nicoll,et al.  Metabotropic glutamate receptor activation causes a rapid redistribution of AMPA receptors , 2001, Neuropharmacology.

[45]  M. Baudry,et al.  Calpain-mediated degradation of PSD-95 in developing and adult rat brain , 2000, Neuroscience Letters.