{"id":{"repo_id":"utswmed","oai_identifier":"oai:utswmed-ir.tdl.org:2152.5/538"},"canonical_url":"https://search.dev.ndltd.org/etd/utswmed/oai:utswmed-ir.tdl.org:2152.5/538","repository":{"repo_id":"utswmed","name":"University of Texas Southwestern Medical Center","base_url":"https://utswmed-ir.tdl.org/server/oai/request"},"display":{"title":"Fragile X Mental Retardation Protein Induces Synapse Loss Through Acute Postsynaptic Translational Regulation","abstract":"Fragile X Syndrome (FXS) is the most common form of inherited mental retardation. The root cause of FXS is loss of the function of a single protein: the Fragile X Mental Retardation Protein (FMRP). FMRP is an RNA-binding protein that plays a complex role in translational regulation. FMRP may be an important regulator of dendritic protein synthesis, which occurs at or near synapses in response to synaptic activity. Many types of long-term synaptic change require local protein synthesis for their induction and/or maintenance, and several protein synthesis-dependent forms of synaptic plasticity are altered in the absence of FMRP. Both human FXS patients and mice lacking FMRP (Fmr1-KO mice) display increased numbers of dendritic spines, the primary sites of excitatory synaptic connections. In addition to increased numbers, the spines of FXS patients and Fmr1-KO mice appear morphologically immature. It was unknown whether FMRP plays a direct, cell-autonomous role in the regulation of synapse number or function. Moreover, the mechanisms through which FMRP might govern neuronal function or number were unclear. I report that acute postsynaptic expression of FMRP in Fmr1-KO neurons results in a decrease in the number of functional and structural synapses without an effect on their synaptic strength or maturational state. Similarly, wild-type neurons endogenously expressing FMRP have fewer synapses than neighboring Fmr1-KO neurons, indicating a clear role for FMRP in the regulation of synapse number. An intact K homology 2 (KH2) RNA-binding domain and dephosphorylation of FMRP at S500 are required for the effects of FMRP on synapse number, indicating that FMRP-dependent translation of mRNA targets of FMRP leads to synapse loss. Furthermore, I demonstrate novel phenotypic interactions of FMRP with the transcription factor MEF2. MEF2 activity in wild-type neurons induces robust synapse loss; however, MEF2 fails to decrease synapse number in Fmr1-KO neurons. A dominant-negative form of MEF2 increases synapse number in WT, but not Fmr1-KO neurons. Finally, when co-expressed with a dominant negative form of MEF2, FMRP fails to induce synapse loss in Fmr1-KO neurons. These data represent novel mechanisms through which FMRP regulates neuronal function and suggest novel therapeutic targets and strategies for FXS treatment.","abstract_html":"Fragile X Syndrome (FXS) is the most common form of inherited mental retardation. The root cause of FXS is loss of the function of a single protein: the Fragile X Mental Retardation Protein (FMRP). FMRP is an RNA-binding protein that plays a complex role in translational regulation. FMRP may be an important regulator of dendritic protein synthesis, which occurs at or near synapses in response to synaptic activity. Many types of long-term synaptic change require local protein synthesis for their induction and/or maintenance, and several protein synthesis-dependent forms of synaptic plasticity are altered in the absence of FMRP. Both human FXS patients and mice lacking FMRP (Fmr1-KO mice) display increased numbers of dendritic spines, the primary sites of excitatory synaptic connections. In addition to increased numbers, the spines of FXS patients and Fmr1-KO mice appear morphologically immature. It was unknown whether FMRP plays a direct, cell-autonomous role in the regulation of synapse number or function. Moreover, the mechanisms through which FMRP might govern neuronal function or number were unclear. I report that acute postsynaptic expression of FMRP in Fmr1-KO neurons results in a decrease in the number of functional and structural synapses without an effect on their synaptic strength or maturational state. Similarly, wild-type neurons endogenously expressing FMRP have fewer synapses than neighboring Fmr1-KO neurons, indicating a clear role for FMRP in the regulation of synapse number. An intact K homology 2 (KH2) RNA-binding domain and dephosphorylation of FMRP at S500 are required for the effects of FMRP on synapse number, indicating that FMRP-dependent translation of mRNA targets of FMRP leads to synapse loss. Furthermore, I demonstrate novel phenotypic interactions of FMRP with the transcription factor MEF2. MEF2 activity in wild-type neurons induces robust synapse loss; however, MEF2 fails to decrease synapse number in Fmr1-KO neurons. A dominant-negative form of MEF2 increases synapse number in WT, but not Fmr1-KO neurons. Finally, when co-expressed with a dominant negative form of MEF2, FMRP fails to induce synapse loss in Fmr1-KO neurons. These data represent novel mechanisms through which FMRP regulates neuronal function and suggest novel therapeutic targets and strategies for FXS treatment.","abstract_has_math":false,"creators":["Pfeiffer, Brad Erich"],"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":2010,"date_issued":"2010-07-12T18:23:24Z","date_published":"2010-07-12T18:23:24Z","updated_at":"2026-07-24T05:52:20Z","subjects":["Fragile X Mental Retardation Protein","Synapses","RNA-Binding Proteins"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["759935314"],"render_values":[{"text":"759935314","href":null,"code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/2152.5/538","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":["Pfeiffer, Brad Erich"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2010-07-12T18:23:24Z","2009-01-14"]},{"key":"dc:type","label":"Dc Type","values":["Thesis","Text","dissertation"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Fragile X Mental Retardation Protein","Synapses","RNA-Binding 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/2152.5/538","759935314"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Fragile X Syndrome (FXS) is the most common form of inherited mental retardation. The root cause of FXS is loss of the function of a single protein: the Fragile X Mental Retardation Protein (FMRP). FMRP is an RNA-binding protein that plays a complex role in translational regulation. FMRP may be an important regulator of dendritic protein synthesis, which occurs at or near synapses in response to synaptic activity. Many types of long-term synaptic change require local protein synthesis for their induction and/or maintenance, and several protein synthesis-dependent forms of synaptic plasticity are altered in the absence of FMRP. Both human FXS patients and mice lacking FMRP (Fmr1-KO mice) display increased numbers of dendritic spines, the primary sites of excitatory synaptic connections. In addition to increased numbers, the spines of FXS patients and Fmr1-KO mice appear morphologically immature. It was unknown whether FMRP plays a direct, cell-autonomous role in the regulation of synapse number or function. Moreover, the mechanisms through which FMRP might govern neuronal function or number were unclear. I report that acute postsynaptic expression of FMRP in Fmr1-KO neurons results in a decrease in the number of functional and structural synapses without an effect on their synaptic strength or maturational state. Similarly, wild-type neurons endogenously expressing FMRP have fewer synapses than neighboring Fmr1-KO neurons, indicating a clear role for FMRP in the regulation of synapse number. An intact K homology 2 (KH2) RNA-binding domain and dephosphorylation of FMRP at S500 are required for the effects of FMRP on synapse number, indicating that FMRP-dependent translation of mRNA targets of FMRP leads to synapse loss. Furthermore, I demonstrate novel phenotypic interactions of FMRP with the transcription factor MEF2. MEF2 activity in wild-type neurons induces robust synapse loss; however, MEF2 fails to decrease synapse number in Fmr1-KO neurons. A dominant-negative form of MEF2 increases synapse number in WT, but not Fmr1-KO neurons. Finally, when co-expressed with a dominant negative form of MEF2, FMRP fails to induce synapse loss in Fmr1-KO neurons. These data represent novel mechanisms through which FMRP regulates neuronal function and suggest novel therapeutic targets and strategies for FXS treatment."]},{"key":"dc:format","label":"Dc Format","values":["Electronic","application/pdf","born digital"]},{"key":"dc:title","label":"Title","values":["Fragile X Mental Retardation Protein Induces Synapse Loss Through Acute Postsynaptic Translational Regulation"]}]}],"canonical_facts":{"dc:contributor":["Huber, Kimberly M."],"dc:creator":["Pfeiffer, Brad Erich"],"dc:date":["2010-07-12T18:23:24Z","2009-01-14"],"dc:description":["Fragile X Syndrome (FXS) is the most common form of inherited mental retardation. The root cause of FXS is loss of the function of a single protein: the Fragile X Mental Retardation Protein (FMRP). FMRP is an RNA-binding protein that plays a complex role in translational regulation. FMRP may be an important regulator of dendritic protein synthesis, which occurs at or near synapses in response to synaptic activity. Many types of long-term synaptic change require local protein synthesis for their induction and/or maintenance, and several protein synthesis-dependent forms of synaptic plasticity are altered in the absence of FMRP. Both human FXS patients and mice lacking FMRP (Fmr1-KO mice) display increased numbers of dendritic spines, the primary sites of excitatory synaptic connections. In addition to increased numbers, the spines of FXS patients and Fmr1-KO mice appear morphologically immature. It was unknown whether FMRP plays a direct, cell-autonomous role in the regulation of synapse number or function. Moreover, the mechanisms through which FMRP might govern neuronal function or number were unclear. I report that acute postsynaptic expression of FMRP in Fmr1-KO neurons results in a decrease in the number of functional and structural synapses without an effect on their synaptic strength or maturational state. Similarly, wild-type neurons endogenously expressing FMRP have fewer synapses than neighboring Fmr1-KO neurons, indicating a clear role for FMRP in the regulation of synapse number. An intact K homology 2 (KH2) RNA-binding domain and dephosphorylation of FMRP at S500 are required for the effects of FMRP on synapse number, indicating that FMRP-dependent translation of mRNA targets of FMRP leads to synapse loss. Furthermore, I demonstrate novel phenotypic interactions of FMRP with the transcription factor MEF2. MEF2 activity in wild-type neurons induces robust synapse loss; however, MEF2 fails to decrease synapse number in Fmr1-KO neurons. A dominant-negative form of MEF2 increases synapse number in WT, but not Fmr1-KO neurons. Finally, when co-expressed with a dominant negative form of MEF2, FMRP fails to induce synapse loss in Fmr1-KO neurons. These data represent novel mechanisms through which FMRP regulates neuronal function and suggest novel therapeutic targets and strategies for FXS treatment."],"dc:format":["Electronic","application/pdf","born digital"],"dc:identifier":["https://hdl.handle.net/2152.5/538","759935314"],"dc:language":["en"],"dc:subject":["Fragile X Mental Retardation Protein","Synapses","RNA-Binding Proteins"],"dc:title":["Fragile X Mental Retardation Protein Induces Synapse Loss Through Acute Postsynaptic Translational Regulation"],"dc:type":["Thesis","Text","dissertation"]},"updated_at":"2026-07-24T05:52:20Z"}