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


Microexons represent the most highly conserved class of alternative splicing, yet their functions are poorly understood. Here, we focus on closely related neuronal microexons overlapping prion-like domains in the translation initiation factors, eIF4G1 and eIF4G3, the splicing of which is activity dependent and frequently disrupted in autism. CRISPR-Cas9 deletion of these microexons selectively upregulates synaptic proteins that control neuronal activity and plasticity and further triggers a gene expression program mirroring that of activated neurons. Mice lacking the Eif4g1 microexon display social behavior, learning, and memory deficits, accompanied by altered hippocampal synaptic plasticity. We provide evidence that the eIF4G microexons function as a translational brake by causing ribosome stalling, through their propensity to promote the coalescence of cytoplasmic granule components associated with translation repression, including the fragile X mental retardation protein FMRP. The results thus reveal an autism-disrupted mechanism by which alternative splicing specializes neuronal translation to control higher order cognitive functioning.

Type Journal
ISBN 1097-4164 (Electronic) 1097-2765 (Linking)
Authors 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-Vallieres, M.; Permanyer, J.; Maier, S.; Georgiou, J.; Irimia, M.; Sonenberg, N.; Forman-Kay, J. D.; Gingras, A. C.; Collingridge, G. L.; Woodin, M. A.; Cordes, S. P.; Blencowe, B. J.
Responsible Garvan Author A/Prof Robert Weatheritt
Published Date 2020-03-19
Published Volume 77
Published Issue 6
Published Pages 1176-1192 e16
Status Published in-print
DOI 10.1016/j.molcel.2020.01.006
URL link to publisher's version
OpenAccess link to author's accepted manuscript version