The lncRNAMalat1is trafficked to the cytoplasm as a localized mRNA encoding a small peptide in neurons

Abstract

AbstractSynaptic function is modulated by local translation of mRNAs that are transported to distal portions of axons and dendrites. The Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is broadly expressed across cell types, almost exclusively as a nuclear non-coding RNA. We found that in differentiating neurons, a portion ofMalat1RNA redistributes to the cytoplasm. Depletion ofMalat1from neurons stimulated expression of particular pre- and post-synaptic proteins, implicatingMalat1in their regulation. NeuronalMalat1is localized to both axons and dendrites in puncta that co-stain with Staufen1 protein, similar to neuronal granules formed by locally translated mRNAs. Ribosome profiling of mouse cortical neurons identified ribosome footprints within a region ofMalat1containing short open reading frames. The upstream-most reading frame (M1) of theMalat1locus was linked to the GFP coding sequence in mouse ES cells. When these gene-edited cells were differentiated into glutamatergic neurons, the M1-GFP fusion protein was expressed. Antibody staining for the M1 peptide confirmed its presence in wildtype neurons, and showed enhancement of M1 expression after synaptic stimulation with KCL. Our results indicate thatMalat1serves as a cytoplasmic coding RNA in the brain that is both modulated by and modulates synaptic function.