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Dissecting Cell-Autonomous Function of Fragile X Mental Retardation Protein in an Auditory Circuit by In Ovo Electroporation
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FMRP phosphorylation and interactions with Cdh1 regulate association with dendritic RNA granules and MEF2-triggered

Julia R Wilkerson1, Marius F Ifrim2, Arielle N Valdez-Sinon3

  • 1Department of Neuroscience, O'Donnell Brain Institute, UT Southwestern Medical Center, Dallas, TX, USA.

Neurobiology of Disease
|April 29, 2023
PubMed

Insights

Myocyte Enhancer Factor 2 (MEF2) regulates synapse elimination by controlling the posttranslational modification and degradation of Fragile X Messenger Ribonucleoprotein (FMRP) via APC/Cdh1, impacting Fragile X Syndrome.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Fragile X Syndrome (FXS) is linked to impaired synapse elimination due to loss of Fragile X Messenger Ribonucleoprotein (FMRP).
  • The molecular mechanisms regulating synapse elimination and FMRP's role are not fully understood.
  • Myocyte Enhancer Factor 2 (MEF2) can induce synapse elimination, but its regulation of FMRP is unclear.

Purpose of the Study:

  • To investigate the role of FMRP posttranslational modifications in MEF2-induced synapse elimination.
  • To elucidate the signaling pathway involving MEF2, FMRP, and APC/Cdh1 in regulating synapse elimination.
  • To determine if FMRP degradation is a key step in synapse elimination.

Main Methods:

  • Organotypic hippocampal slice cultures from Fmr1 knockout mice.
  • Expression of active MEF2 to induce synapse elimination.
  • Postsynaptic reexpression of FMRP.
  • Analysis of FMRP phosphorylation at S499.
  • Ubiquitination assays using bimolecular ubiquitin-mediated fluorescence complementation (UbFC).
  • Interaction studies with APC/Cdh1.

Main Results:

  • MEF2-induced synapse elimination is impaired in Fmr1 knockout neurons and rescued by FMRP reexpression.
  • Both phosphorylation and dephosphorylation of FMRP at S499 are crucial for synapse elimination.
  • FMRP interacts with the E3 ligase APC/Cdh1.
  • MEF2 promotes FMRP ubiquitination and degradation in a manner dependent on APC/Cdh1 activity.
  • MEF2-induced synapse elimination requires FMRP degradation.

Conclusions:

  • MEF2 regulates synapse elimination by modulating FMRP's posttranslational status.
  • FMRP degradation, mediated by APC/Cdh1, is a critical step in MEF2-induced synapse elimination.
  • This pathway provides a molecular link between MEF2, FMRP, and synapse elimination, offering insights into FXS pathogenesis.
Keywords:
Cdh1FMRPHippocampal CA1MEF2Synapse elimination

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