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Neuronal activity rapidly reprograms dendritic translation via eIF4G2:uORF binding

ABSTRACT: Learning and memory require activity-induced changes in dendritic translation, but which messenger RNAs (mRNAs) are involved and how they are regulated are unclear. Here, to monitor how depolarization impacts local dendritic biology, we employed a dendritically-targeted proximity labeling approach, followed by cross-linking immunoprecipitation (CLIP), ribosome profiling, and mass spectrometry. Depolarization of primary cortical neurons with KCl or the glutamate agonist DHPG causes rapid reprogramming of dendritic protein expression, where changes in dendritic mRNAs and proteins are weakly correlated. For a subset of pre-localized messages, depolarization increases translation of upstream open reading frames (uORFs) and their downstream coding sequences, enabling localized production of proteins involved in long term potentiation, cell signaling, and energy metabolism. This activity-dependent translation is accompanied by the phosphorylation and recruitment of the non-canonical translation initiation factor eIF4G2, and the translated uORFs are sufficient to confer depolarization-induced, eIF4G2-dependent translational control. These studies uncover an unanticipated mechanism by which activity-dependent uORF translational control by eIF4G2 couples activity to local dendritic remodeling.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cerebral Cortex Neuron, Brain

SUBMITTER: Ezgi Hacisuleyman

LAB HEAD: Robert B Darnell

PROVIDER: PXD050222 | Pride | 2024-04-02

REPOSITORIES: Pride

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	Hacisuleyman_dep_pan_minus_1_a.raw	Raw
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