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RNA-binding FMRP and Staufen sequentially regulate the Coracle scaffold to control synaptic glutamate receptor and

Chunzhu Song1, Shannon N Leahy1, Emma M Rushton1

  • 1Department of Biological Sciences, Vanderbilt University and Medical Center, Nashville, TN 37235, USA.

Development (Cambridge, England)
|April 8, 2022
PubMed

Insights

Fragile X mental retardation protein (FMRP) and Staufen regulate synapse development by controlling postsynaptic Coracle expression. This pathway influences glutamate receptor levels and neurotransmission strength at the Drosophila neuromuscular junction.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Fragile X mental retardation protein (FMRP) and Staufen are key mRNA-binding proteins involved in regulating synaptic function.
  • Both proteins influence synaptic bouton formation and glutamate receptor (GluR) levels at the Drosophila neuromuscular junction (NMJ).

Purpose of the Study:

  • To investigate whether FMRP and Staufen function jointly in a common mechanism regulating synapse development.
  • To elucidate the molecular pathway involving FMRP, Staufen, and Coracle in synapse formation and function.

Main Methods:

  • Utilized Drosophila melanogaster models with mutations in dfmr1 and staufen genes.
  • Employed cell-targeted RNA interference and immunoprecipitation techniques.
  • Analyzed synaptic bouton formation, GluRIIA accumulation, and neurotransmission strength.

Main Results:

  • dfmr1 and staufen mutants, as well as double mutants, showed increased synaptic bouton formation and GluRIIA accumulation.
  • FMRP binds staufen mRNA, stabilizing postsynaptic transcripts, and Staufen binds coracle mRNA.
  • FMRP and Staufen act sequentially to regulate postsynaptic Coracle expression, which controls GluRIIA levels and synaptic bouton development.
  • Mutants in dfmr1, staufen, and coracle exhibited elevated neurotransmission strength.
  • FMRP, Staufen, and Coracle were found to suppress pMad activation, linking postsynaptic GluRIIA levels to presynaptic bouton development.

Conclusions:

  • An FMRP-Staufen-Coracle-GluRIIA-pMad pathway regulates structural and functional synapse development at the Drosophila NMJ.
  • This pathway highlights a coordinated mechanism for controlling synaptic plasticity and neurotransmission.
Keywords:
FMRPFragile X syndromeNeuromuscular junctionNeurotransmissionSynapseSynaptogenesis

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