A Study on an FMRP-Mediated Translational Switch in the MGluR-Triggered Translation of Arc and Synaptic Plasticity
dc.contributor.advisor | Huber, Kimberly M. | en |
dc.creator | Niere, Farr | en |
dc.date.accessioned | 2012-07-16T18:50:32Z | |
dc.date.available | 2012-07-16T18:50:32Z | |
dc.date.issued | 2012-07-16 | |
dc.description.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. | en |
dc.identifier.oclc | 812525362 | |
dc.identifier.uri | https://hdl.handle.net/2152.5/1002 | |
dc.language.iso | en | en |
dc.subject | Fragile X Mental Retardation Protein | en |
dc.subject | Receptors, Metabotropic Glutamate | en |
dc.subject | Cytoskeletal Proteins | en |
dc.title | A Study on an FMRP-Mediated Translational Switch in the MGluR-Triggered Translation of Arc and Synaptic Plasticity | en |
dc.type | Thesis | en |
dc.type.material | Text | en |
thesis.date.available | 2014-07-06 | |
thesis.degree.department | Graduate School of Biomedical Sciences | en |
thesis.degree.discipline | Neuroscience | en |
thesis.degree.grantor | UT Southwestern Medical Center | en |
thesis.degree.level | Doctoral | en |
thesis.degree.name | Doctor of Philosophy | en |