Microexon splicing and translation in ASD

Alternative splicing of microexons (short exons of 3–27 nucleotides) has previously been linked to autism spectrum disorder (ASD), although few studies of the functional impact of individual microexons have been carried out. A new study of particular microexons in genes encoding translation initiation factors fills this gap and firmly links microexon splicing to translation, synaptic plasticity and ASD-relevant behaviors.

The work was supported in part by a Pilot Award to SFARI Investigator Benjamin Blencowe. The Blencowe lab had previously identified a network of neuronal microexons whose expression was disrupted in postmortem ASD brains (Irimia et al., Cell, 2014). The focus in the present study was on specific microexons in two paralogs of the eukaryotic translation initiation factor Eif4g. The authors confirmed that Eif4g microexons, like other neuronal microexons, are regulated by the protein SRRM4 and that their splicing is dependent on neuronal activity. CRISPR-Cas9-based editing of these microexons further showed that they, in turn, regulate the expression of a number of synaptic proteins, including the NMDA receptor subunit GluN1. Skipping of the Eif4g microexons was associated with increased synaptic protein expression, with downstream effects on neuronal plasticity, social behavior, and learning and memory. Of note, the mechanism by which the microexons regulate translation seemed to involve the regulation of granule formation, including FMRP, which promoted ribosome stalling and reduced protein production.

The study by Blencowe and colleagues is reminiscent of another recent study (Parras et al., Nature, 2018), which demonstrated that a microexon in the gene-encoding cytoplasmic polyadenylation binding element 4 (CPEB4) is critical for normal levels of translation and is altered in ASD. It will no doubt be of interest to examine other microexons in translation-associated genes in the context of ASD.

Loss of Eif4g1 microexon affects synaptic function. Results from slice cultures of the CA1 region of the hippocampus from mice that are wild-type (black) or mice that lack the Eif4g1 microexon (red). On the left are representative traces of whole-cell voltage-clamp recordings showing an increase in the amplitude of spontaneous inhibitory postsynaptic currents in the microexon-deficient mice. These results are quantified on the right (there is no significant difference in frequency, as quantified on the far right). Image from Gonatopoulos-Pournatzis T. et al. (2020).


Autism-misregulated eIF4G microexons control synaptic translation and higher order cognitive functions.

Gonatopoulos-Pournatzis T., Niibori R., Salter E.W., Weatheritt R.J., Tsang B., Farhangmehr S., Liang X., Braunschweig U., Roth J., Zhang S., Henderson T., Sharma E., Quesnel-Vallières M., Permanyer J., Maier S., Georgiou J., Irimia M., Sonenberg N., Forman-Kay J.D., Gingras A.C., Collingridge G.L., Woodin M., Cordes S.P., Blencowe B.

Mol. Cell. 77, 1176-1192 (March 19, 2020) PubMed

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