YTHDF1 mediates translational control by m6A mRNA methylation in adaptation to environmental challenges

Abstract

AbstractAnimals adapt to environmental challenges with long-term changes at the behavioral, circuit, cellular, and synaptic levels which often require new protein synthesis. The discovery of reversible N6-methyladenosine (m6A) modifications of mRNA has revealed an important layer of post-transcriptional regulation which affects almost every phase of mRNA metabolism and therefore translational control. Manyin vitroandin vivostudies have demonstrated the significant role of m6A in cell differentiation and survival, but its role in adult neurons is understudied. We used cell-type specific gene deletion ofMettl14,which encodes one of the subunits of the m6A methyltransferase, andYthdf1, which encodes one of the cytoplasmic m6A reader proteins, in dopamine D1 receptor expressing or D2 receptor expressing neurons.Mettl14orYthdf1deficiency blunted responses to environmental challenges at the behavioral, cellular, and molecular levels. In three different behavioral paradigms, gene deletion of eitherMettl14orYthdf1in D1 neurons impaired D1-dependent learning, whereas gene deletion of eitherMettl14orYthdf1in D2 neurons impaired D2-dependent learning. At the cellular level, modulation of D1 and D2 neuron firing in response to changes in environments was blunted in all three behavioral paradigms in mutant mice.Ythdf1deletion resembled impairment caused byMettl14deletion in a cell type-specific manner, suggesting YTHDF1 is the main mediator of the functional consequences of m6A mRNA methylation in the striatum. At the molecular level, while striatal neurons in control mice responded to elevated cAMP by increasingde novoprotein synthesis, striatal neurons inYthdf1knockout mice didn’t. Finally, boosting dopamine release by cocaine drastically increased YTHDF1 binding to many mRNA targets in the striatum, especially those that encode structural proteins, suggesting the initiation of long-term neuronal and/or synaptic structural changes. While the m6A-YTHDF1 pathway has similar functional significance at cellular level, its cell type specific deficiency in D1 and D2 neurons often resulted in contrasting behavioral phenotypes, allowing us to cleanly dissociate the opposing yet cooperative roles of D1 and D2 neurons.