TY - UNPB
T1 - eIF4E phosphorylation recruits β-catenin to mRNA cap and selectively promotes Wnt pathway translation in dentate gyrus LTP maintenance in vivo
AU - Patil, Sudarshan
AU - Chalkiadaki, Kleanthi
AU - Mergiya, Tadiwos Feyissa
AU - Simbriger, Konstanze
AU - Amorim, Inês S.
AU - Akerkar, Shreeram
AU - Gkogkas, Christos G.
AU - Bramham, Clive R.
PY - 2022/9/28
Y1 - 2022/9/28
N2 - 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
AB - 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
U2 - 10.1101/2022.09.28.509312
DO - 10.1101/2022.09.28.509312
M3 - Preprint
BT - eIF4E phosphorylation recruits β-catenin to mRNA cap and selectively promotes Wnt pathway translation in dentate gyrus LTP maintenance in vivo
PB - bioRxiv
ER -