{"id":{"repo_id":"utswmed","oai_identifier":"oai:utswmed-ir.tdl.org:2152.5/1002"},"canonical_url":"https://search.dev.ndltd.org/etd/utswmed/oai:utswmed-ir.tdl.org:2152.5/1002","repository":{"repo_id":"utswmed","name":"University of Texas Southwestern Medical Center","base_url":"https://utswmed-ir.tdl.org/server/oai/request"},"display":{"title":"A Study on an FMRP-Mediated Translational Switch in the MGluR-Triggered Translation of Arc and Synaptic Plasticity","abstract":"The group 1 metabotropic glutamate receptor (mGluR)-stimulated protein synthesis and long-term synaptic depression (mGluR-LTD) are altered in a mouse model of Fragile X Syndrome, Fmr1 knockout (KO) mouse. Fmr1 encodes the Fragile X mental retardation protein (FMRP), a dendritic RNA-binding protein that functions, in part, as a translational suppressor. It is unknown if and how FMRP acutely regulates LTD and/or the rapid synthesis of new proteins required for LTD, such as the activity-regulated cytoskeletal-associated protein (Arc). The protein phosphatase PP2A dephosphorylates FMRP, which contributes to the translational activation of some target mRNAs. Here, I report that PP2A and the dephosphorylation of FMRP at S500 are required for an mGluR-induced, rapid increase in dendritic Arc protein and LTD in rat and mouse hippocampal neurons. In the Fmr1 KO neurons, basal, dendritic Arc protein levels and mGluR-LTD are enhanced, and the mGluR-triggered Arc synthesis is absent. A lentiviral-mediated expression of the wildtype FMRP in Fmr1 KO neurons suppresses basal, dendritic Arc levels and mGluR-LTD, and restores the rapid mGluR-triggered Arc synthesis. A phosphomimic of FMRP (S500D) suppresses steady state dendritic Arc levels but does not rescue the mGluR-induced Arc synthesis. A dephosphomimic of FMRP (S500A) neither suppresses the basal, dendritic Arc levels nor supports the mGluR-induced Arc synthesis. Accordingly, expressing the S500D-FMRP in Fmr1 KO neurons suppresses mGluR-LTD, whereas the S500A-FMRP has no effect. These data support a model whereby a phosphorylated FMRP at S500 functions to suppress the steady state and the mGluR-induced translation of Arc and mGluR-LTD. However, upon mGluR activation of PP2A, FMRP is rapidly dephosphorylated which contributes to the rapid, new synthesis of Arc and mGluR-LTD.","abstract_html":"The group 1 metabotropic glutamate receptor (mGluR)-stimulated protein synthesis and long-term synaptic depression (mGluR-LTD) are altered in a mouse model of Fragile X Syndrome, Fmr1 knockout (KO) mouse. Fmr1 encodes the Fragile X mental retardation protein (FMRP), a dendritic RNA-binding protein that functions, in part, as a translational suppressor. It is unknown if and how FMRP acutely regulates LTD and/or the rapid synthesis of new proteins required for LTD, such as the activity-regulated cytoskeletal-associated protein (Arc). The protein phosphatase PP2A dephosphorylates FMRP, which contributes to the translational activation of some target mRNAs. Here, I report that PP2A and the dephosphorylation of FMRP at S500 are required for an mGluR-induced, rapid increase in dendritic Arc protein and LTD in rat and mouse hippocampal neurons. In the Fmr1 KO neurons, basal, dendritic Arc protein levels and mGluR-LTD are enhanced, and the mGluR-triggered Arc synthesis is absent. A lentiviral-mediated expression of the wildtype FMRP in Fmr1 KO neurons suppresses basal, dendritic Arc levels and mGluR-LTD, and restores the rapid mGluR-triggered Arc synthesis. A phosphomimic of FMRP (S500D) suppresses steady state dendritic Arc levels but does not rescue the mGluR-induced Arc synthesis. A dephosphomimic of FMRP (S500A) neither suppresses the basal, dendritic Arc levels nor supports the mGluR-induced Arc synthesis. Accordingly, expressing the S500D-FMRP in Fmr1 KO neurons suppresses mGluR-LTD, whereas the S500A-FMRP has no effect. These data support a model whereby a phosphorylated FMRP at S500 functions to suppress the steady state and the mGluR-induced translation of Arc and mGluR-LTD. However, upon mGluR activation of PP2A, FMRP is rapidly dephosphorylated which contributes to the rapid, new synthesis of Arc and mGluR-LTD.","abstract_has_math":false,"creators":["Niere, Farr"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":["Huber, Kimberly M."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2012,"date_issued":"2012-07-16T18:50:32Z","date_published":"2012-07-16T18:50:32Z","updated_at":"2026-07-24T05:52:29Z","subjects":["Fragile X Mental Retardation Protein","Receptors, Metabotropic Glutamate","Cytoskeletal Proteins"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["812525362"],"render_values":[{"text":"812525362","href":null,"code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/2152.5/1002","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Huber, Kimberly M."]},{"key":"dc:creator","label":"Author","values":["Niere, Farr"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2012-07-16T18:50:32Z","2012-07-16"]},{"key":"dc:type","label":"Dc Type","values":["Thesis","Text"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Fragile X Mental Retardation Protein","Receptors, Metabotropic Glutamate","Cytoskeletal Proteins"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://hdl.handle.net/2152.5/1002","812525362"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["The group 1 metabotropic glutamate receptor (mGluR)-stimulated protein synthesis and long-term synaptic depression (mGluR-LTD) are altered in a mouse model of Fragile X Syndrome, Fmr1 knockout (KO) mouse. Fmr1 encodes the Fragile X mental retardation protein (FMRP), a dendritic RNA-binding protein that functions, in part, as a translational suppressor. It is unknown if and how FMRP acutely regulates LTD and/or the rapid synthesis of new proteins required for LTD, such as the activity-regulated cytoskeletal-associated protein (Arc). The protein phosphatase PP2A dephosphorylates FMRP, which contributes to the translational activation of some target mRNAs. Here, I report that PP2A and the dephosphorylation of FMRP at S500 are required for an mGluR-induced, rapid increase in dendritic Arc protein and LTD in rat and mouse hippocampal neurons. In the Fmr1 KO neurons, basal, dendritic Arc protein levels and mGluR-LTD are enhanced, and the mGluR-triggered Arc synthesis is absent. A lentiviral-mediated expression of the wildtype FMRP in Fmr1 KO neurons suppresses basal, dendritic Arc levels and mGluR-LTD, and restores the rapid mGluR-triggered Arc synthesis. A phosphomimic of FMRP (S500D) suppresses steady state dendritic Arc levels but does not rescue the mGluR-induced Arc synthesis. A dephosphomimic of FMRP (S500A) neither suppresses the basal, dendritic Arc levels nor supports the mGluR-induced Arc synthesis. Accordingly, expressing the S500D-FMRP in Fmr1 KO neurons suppresses mGluR-LTD, whereas the S500A-FMRP has no effect. These data support a model whereby a phosphorylated FMRP at S500 functions to suppress the steady state and the mGluR-induced translation of Arc and mGluR-LTD. However, upon mGluR activation of PP2A, FMRP is rapidly dephosphorylated which contributes to the rapid, new synthesis of Arc and mGluR-LTD."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["A Study on an FMRP-Mediated Translational Switch in the MGluR-Triggered Translation of Arc and Synaptic Plasticity"]}]}],"canonical_facts":{"dc:contributor":["Huber, Kimberly M."],"dc:creator":["Niere, Farr"],"dc:date":["2012-07-16T18:50:32Z","2012-07-16"],"dc:description":["The group 1 metabotropic glutamate receptor (mGluR)-stimulated protein synthesis and long-term synaptic depression (mGluR-LTD) are altered in a mouse model of Fragile X Syndrome, Fmr1 knockout (KO) mouse. Fmr1 encodes the Fragile X mental retardation protein (FMRP), a dendritic RNA-binding protein that functions, in part, as a translational suppressor. It is unknown if and how FMRP acutely regulates LTD and/or the rapid synthesis of new proteins required for LTD, such as the activity-regulated cytoskeletal-associated protein (Arc). The protein phosphatase PP2A dephosphorylates FMRP, which contributes to the translational activation of some target mRNAs. Here, I report that PP2A and the dephosphorylation of FMRP at S500 are required for an mGluR-induced, rapid increase in dendritic Arc protein and LTD in rat and mouse hippocampal neurons. In the Fmr1 KO neurons, basal, dendritic Arc protein levels and mGluR-LTD are enhanced, and the mGluR-triggered Arc synthesis is absent. A lentiviral-mediated expression of the wildtype FMRP in Fmr1 KO neurons suppresses basal, dendritic Arc levels and mGluR-LTD, and restores the rapid mGluR-triggered Arc synthesis. A phosphomimic of FMRP (S500D) suppresses steady state dendritic Arc levels but does not rescue the mGluR-induced Arc synthesis. A dephosphomimic of FMRP (S500A) neither suppresses the basal, dendritic Arc levels nor supports the mGluR-induced Arc synthesis. Accordingly, expressing the S500D-FMRP in Fmr1 KO neurons suppresses mGluR-LTD, whereas the S500A-FMRP has no effect. These data support a model whereby a phosphorylated FMRP at S500 functions to suppress the steady state and the mGluR-induced translation of Arc and mGluR-LTD. However, upon mGluR activation of PP2A, FMRP is rapidly dephosphorylated which contributes to the rapid, new synthesis of Arc and mGluR-LTD."],"dc:format":["application/pdf"],"dc:identifier":["https://hdl.handle.net/2152.5/1002","812525362"],"dc:language":["en"],"dc:subject":["Fragile X Mental Retardation Protein","Receptors, Metabotropic Glutamate","Cytoskeletal Proteins"],"dc:title":["A Study on an FMRP-Mediated Translational Switch in the MGluR-Triggered Translation of Arc and Synaptic Plasticity"],"dc:type":["Thesis","Text"]},"updated_at":"2026-07-24T05:52:29Z"}