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Description:
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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 . |