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bioRxiv · 10.1101/2022.09.28.509312

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

Patil, S.·Chalkiadaki, K.·Mergiya, T.-F.·Simbriger, K.·Amorim, I. S.·Akerkar, S.·Gkogkas, C. G.·Bramham, C. R.
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Abstract

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, {beta}-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 highlightsO_LISynaptic activity-induced eIF4E phosphorylation controls DG-LTP maintenance in vivo C_LIO_LIeIF4E phosphorylation triggers release of translational repressors from cap complex C_LIO_LIeIF4E phosphorylation recruits {beta}-catenin to cap complex C_LIO_LIeIF4E phosphorylation selectively enhances translation of Wnt pathway C_LI

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Patil, S., Chalkiadaki, K., Mergiya, T.-F., Simbriger, K., Amorim, I. S., Akerkar, S., Gkogkas, C. G., Bramham, C. R.. 2022-09-28. eIF4E phosphorylation recruits β-catenin to mRNA cap and selectively promotes Wnt pathway translation in dentate gyrus LTP maintenance in vivo. https://doi.org/10.1101/2022.09.28.509312

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