Translational regulation of NeuroD1 expression by FMRP: involvement in glutamatergic neuronal differentiation of cultured rat primary neural progenitor cells

Cell Mol Neurobiol. 2014 Mar;34(2):297-305. doi: 10.1007/s10571-013-0014-9. Epub 2013 Dec 12.


Fragile X mental retardation protein (FMRP) is encoded by Fmr1 gene in which mutation is known to cause fragile X syndrome characterized by mental impairment and other psychiatric symptoms similar to autism spectrum disorders. FMRP plays important roles in cellular mRNA biology such as transport, stability, and translation as an RNA-binding protein. In the present study, we identified potential role of FMRP in the neural differentiation, using cortical neural progenitor cells from Sprague-Dawley rat. We newly found NeuroD1, an essential regulator of glutamatergic neuronal differentiation, as a new mRNA target interacting with FMRP in co-immunoprecipitation experiments. We also identified FMRP as a regulator of neuronal differentiation by modulating NeuroD1 expression. Down-regulation of FMRP by siRNA also increased NeuroD1 expression along with increased pre- and post-synaptic development of glutamatergic neuron, as evidenced by Western blot and immunocytochemistry. On the contrary, cells harboring FMRP over-expression construct showed decreased NeuroD1 expression. Treatment of cultured neural precursor cells with a histone deacetylase inhibitor, valproic acid known as an inducer of hyper-glutamatergic neuronal differentiation, down-regulated the expression of FMRP, and induced NeuroD1 expression. Our study suggests that modulation of FMRP expression regulates neuronal differentiation by interaction with its binding target mRNA, and provides an example of the gene and environmental interaction regulating glutamatergic neuronal differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Cell Differentiation* / drug effects
  • Cell Differentiation* / genetics
  • Cells, Cultured
  • Female
  • Fragile X Mental Retardation Protein / metabolism*
  • Gene Expression Regulation* / drug effects
  • Gene Knockdown Techniques
  • Glutamates / metabolism
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Neural Stem Cells / cytology*
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / metabolism
  • Neurons / cytology*
  • Neurons / drug effects
  • Neurons / metabolism
  • Protein Binding / drug effects
  • Protein Biosynthesis* / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Synapses / drug effects
  • Synapses / metabolism
  • Valproic Acid / pharmacology


  • Basic Helix-Loop-Helix Transcription Factors
  • Glutamates
  • Nerve Tissue Proteins
  • RNA, Messenger
  • Fragile X Mental Retardation Protein
  • Neurogenic differentiation factor 1
  • Valproic Acid