eIF4E phosphorylation recruits β-catenin to mRNA cap and selectively promotes Wnt pathway translation in dentate gyrus LTP maintenance in vivo

Sudarshan Patil, Kleanthi Chalkiadaki, Tadiwos Feyissa Mergiya, Konstanze Simbriger, Inês S. Amorim, Shreeram Akerkar, Christos G. Gkogkas, Clive R. Bramham

Research output: Working paperPreprint

Abstract / Description of output

The mRNA cap-binding protein, eukaryotic initiation factor 4E (eIF4E), is crucial for translation and regulated by Ser209 phosphorylation. However, the biochemical and physiological role of eIF4E phosphorylation in translational control of long-term synaptic plasticity is unknown. We demonstrate that phospho-ablated Eif4eS209A knockin mice are profoundly impaired in dentate gyrus LTP maintenance in vivo, while basal perforant path-evoked transmission and LTP induction are intact. mRNA cap-pulldown assays show that phosphorylation is required for synaptic activity-induced removal of translational repressors from eIF4E, allowing initiation complex formation. Using ribosome profiling, we identified selective, phospho-eIF4E-dependent translation of the Wnt signaling pathway in in vivo LTP. Surprisingly, the canonical Wnt effector, β-catenin, was massively recruited to the eIF4E cap complex following LTP induction in wild-type, but not Eif4eS209A, mice. These results demonstrate a critical role for activity-evoked eIF4E phosphorylation in dentate gyrus LTP maintenance, bidirectional remodeling of the mRNA cap-binding complex, and mRNA-specific translational control linked to Wnt pathway. Key highlightsSynaptic activity-induced eIF4E phosphorylation controls DG-LTP maintenance in vivoeIF4E phosphorylation triggers release of translational repressors from cap complexeIF4E phosphorylation recruits β-catenin to cap complexeIF4E phosphorylation selectively enhances translation of Wnt pathway
Original languageEnglish
PublisherbioRxiv
DOIs
Publication statusPublished - 28 Sept 2022

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