eIF4E phosphorylation recruits β-catenin to mRNA cap and promotes Wnt pathway translation in dentate gyrus LTP maintenance
Sudarshan Patil,
Kleanthi Chalkiadaki,
Tadiwos F. Mergiya,
Konstanze Krimbacher,
Inês S. Amorim,
Shreeram Akerkar,
Christos G. Gkogkas,
Clive R. Bramham
Affiliations
Sudarshan Patil
Department of Biomedicine Jonas Lies vei 91, University of Bergen, 5009 Bergen, Norway; Corresponding author
Kleanthi Chalkiadaki
Biomedical Research Institute, Foundation for Research and Technology-Hellas, 45110 Ioannina, Greece
Tadiwos F. Mergiya
Department of Biomedicine Jonas Lies vei 91, University of Bergen, 5009 Bergen, Norway; Mohn Research Center for the Brain, University of Bergen, Bergen, Norway
Konstanze Krimbacher
Center for Discovery Brain Sciences, University of Edinburgh, EH8 9XD Edinburgh, UK
Inês S. Amorim
Center for Discovery Brain Sciences, University of Edinburgh, EH8 9XD Edinburgh, UK
Shreeram Akerkar
Department of Biomedicine Jonas Lies vei 91, University of Bergen, 5009 Bergen, Norway
Christos G. Gkogkas
Biomedical Research Institute, Foundation for Research and Technology-Hellas, 45110 Ioannina, Greece; Corresponding author
Clive R. Bramham
Department of Biomedicine Jonas Lies vei 91, University of Bergen, 5009 Bergen, Norway; Mohn Research Center for the Brain, University of Bergen, Bergen, Norway; Corresponding author
Summary: 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, whereas 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 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, remodeling of the mRNA cap-binding complex, and specific translation of the Wnt pathway.
