title: FMRP-dependent Mdm2 dephosphorylation is required for MEF2-induced synapse elimination.
abstract: The Myocyte Enhancer Factor 2 (MEF2) transcription factors suppress an excitatory synapse number by promoting degradation of the synaptic scaffold protein, postsynaptic density protein 95 (PSD-95), a process that is deficient in the mouse model of Fragile X Syndrome, Fmr1 KO. How MEF2 activation results in PSD-95 degradation and why this is defective in Fmr1 KO neurons is unknown. Here we report that MEF2 induces a Protein phosphatase 2A (PP2A)-mediated dephosphorylation of murine double minute-2 (Mdm2), the ubiquitin E3 ligase for PSD-95, which results in nuclear export and synaptic accumulation of Mdm2 as well as PSD-95 degradation and synapse elimination. In Fmr1 KO neurons, Mdm2 is hyperphosphorylated, nuclear localized basally, and unaffected by MEF2 activation, which our data suggest due to an enhanced interaction with Eukaryotic Elongation Factor 1α (EF1α), whose protein levels are elevated in Fmr1 KO. Expression of a dephosphomimetic of Mdm2 rescues PSD-95 ubiquitination, degradation and synapse elimination in Fmr1 KO neurons. This work reveals detailed mechanisms of synapse elimination in health and a developmental brain disorder.
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USA.|Department of Molecular and Integrative Physiology, School of Molecular and Cellular Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.|Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: Nien-Pei
authors.initials: NP
authors.lastname: Tsai
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Julia R
authors.initials: JR
authors.lastname: Wilkerson
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Weirui
authors.initials: W
authors.lastname: Guo
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Huber
mesh_terms: D000818:Animals; D003712:Dendrites / Q000378:metabolism / Q000473:pathology; D000076122:Disks Large Homolog 4 Protein; D015977:Eukaryotic Initiation Factor-1 / Q000235:genetics; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000235:genetics* / Q000473:pathology; D051528:Guanylate Kinases / Q000235:genetics*; D006801:Humans; D064326:MEF2 Transcription Factors / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000235:genetics; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D013569:Synapses / Q000235:genetics / Q000473:pathology; D054875:Ubiquitination / Q000235:genetics
chemical_list: D000076122:Disks Large Homolog 4 Protein; D015977:Eukaryotic Initiation Factor-1; D051860:Fragile X Messenger Ribonucleoprotein 1; D051528:Guanylate Kinases; D064326:MEF2 Transcription Factors; D008565:Membrane Proteins; D054648:Protein Phosphatase 2; D051736:Proto-Oncogene Proteins c-mdm2; C501447:Dlg4 protein, mouse; C497684:Fmr1 protein, mouse; C497207:Mdm2 protein, mouse