FMRP-dependent Mdm2 dephosphorylation is required for MEF2-induced synapse elimination

Nien-Pei Tsai, Julia R. Wilkerson, Weirui Guo, Kimberly M. Huber

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)293-304
Number of pages12
JournalHuman molecular genetics
Volume26
Issue number2
DOIs
StatePublished - Jan 1 2017

Fingerprint

MEF2 Transcription Factors
Synapses
Neurons
Proteolysis
Peptide Elongation Factor 1
Fragile X Syndrome
Protein Phosphatase 2
Ubiquitin-Protein Ligases
Cell Nucleus Active Transport
Ubiquitination
Brain Diseases
Proteins
Transcription Factors
postsynaptic density proteins
Health

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

FMRP-dependent Mdm2 dephosphorylation is required for MEF2-induced synapse elimination. / Tsai, Nien-Pei; Wilkerson, Julia R.; Guo, Weirui; Huber, Kimberly M.

In: Human molecular genetics, Vol. 26, No. 2, 01.01.2017, p. 293-304.

Research output: Contribution to journalArticle

Tsai, Nien-Pei ; Wilkerson, Julia R. ; Guo, Weirui ; Huber, Kimberly M. / FMRP-dependent Mdm2 dephosphorylation is required for MEF2-induced synapse elimination. In: Human molecular genetics. 2017 ; Vol. 26, No. 2. pp. 293-304.
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