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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
Summary
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/SRRM4More Related Videos
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