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Autism-Misregulated eIF4G Microexons Control Synaptic Translation and Higher Order Cognitive Functions

Thomas Gonatopoulos-Pournatzis1, Rieko Niibori2, Eric W Salter3

  • 1Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.

Molecular Cell
|January 31, 2020
PubMed

Insights

Neuronal microexons in translation factors, disrupted in autism, act as a translational brake. Their deletion upregulates synaptic proteins, impacting social behavior, learning, and memory in mice.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Microexons are highly conserved but functionally understudied alternative splicing events.
  • Neuronal microexons in eIF4G1/eIF4G3, linked to autism, overlap prion-like domains.
  • Their splicing is activity-dependent and frequently disrupted in autism spectrum disorder.

Purpose of the Study:

  • To investigate the function of neuronal microexons in eIF4G1 and eIF4G3.
  • To elucidate the mechanism by which these microexons regulate neuronal translation and cognitive function.
  • To understand the role of microexon disruption in autism.

Main Methods:

  • CRISPR-Cas9 gene editing to delete specific microexons.
  • Analysis of synaptic protein expression and gene expression programs.
  • Behavioral testing in mice (social behavior, learning, memory).
  • Assessment of hippocampal synaptic plasticity.

Main Results:

  • Microexon deletion selectively upregulated synaptic proteins, mimicking activated neurons.
  • Mice lacking the Eif4g1 microexon exhibited social, learning, and memory deficits.
  • Altered hippocampal synaptic plasticity was observed in knockout mice.
  • eIF4G microexons function as a translational brake, causing ribosome stalling via cytoplasmic granule component coalescence (including FMRP).

Conclusions:

  • Alternative splicing of eIF4G microexons regulates neuronal translation and higher-order cognitive functions.
  • Disruption of this microexon-mediated translational control is a mechanism implicated in autism.
  • This study reveals a novel link between alternative splicing, translational regulation, and cognitive deficits in neurological disorders.
Keywords:
Alternative SplicingAutism Spectrum DisorderFMRPFragile X SyndromeLearning and MemoryMicroexonsPhase SeparationSocial BehavioureIF4G Translation Initiation FactorsmRNP granulesnSR100/SRRM4

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