FXR2P Exerts a Positive Translational Control and Is Required for the Activity-Dependent Increase of PSD95 Expression

J Neurosci. 2015 Jun 24;35(25):9402-8. doi: 10.1523/JNEUROSCI.4800-14.2015.

Abstract

In brain, specific RNA-binding proteins (RBPs) associate with localized mRNAs and function as regulators of protein synthesis at synapses exerting an indirect control on neuronal activity. Thus, the Fragile X Mental Retardation protein (FMRP) regulates expression of the scaffolding postsynaptic density protein PSD95, but the mode of control appears to be different from other FMRP target mRNAs. Here, we show that the fragile X mental retardation-related protein 2 (FXR2P) cooperates with FMRP in binding to the 3'-UTR of mouse PSD95/Dlg4 mRNA. Absence of FXR2P leads to decreased translation of PSD95/Dlg4 mRNA in the hippocampus, implying a role for FXR2P as translation activator. Remarkably, mGluR-dependent increase of PSD95 synthesis is abolished in neurons lacking Fxr2. Together, these findings show a coordinated regulation of PSD95/Dlg4 mRNA by FMRP and FXR2P that ultimately affects its fine-tuning during synaptic activity.

Keywords: FMRP; FXR2P; PSD95; RNA binding proteins; mRNA translation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Disks Large Homolog 4 Protein
  • Gene Expression Regulation / physiology*
  • Guanylate Kinases / biosynthesis*
  • Guanylate Kinases / genetics
  • Immunohistochemistry
  • Immunoprecipitation
  • Membrane Proteins / biosynthesis*
  • Membrane Proteins / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neuronal Plasticity / physiology*
  • Neurons / metabolism*
  • Protein Biosynthesis / physiology
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*

Substances

  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • FXR2 protein, mouse
  • Membrane Proteins
  • RNA-Binding Proteins
  • Guanylate Kinases