The lncRNA Malat1 is trafficked to the cytoplasm as a localized mRNA encoding a small peptide in neurons

Abstract

In this study, Xiao et al. show that a portion of Malat1 transcripts is exported to the cytoplasm during neuronal development. They demonstrate that depletion of neuronal Malat1 affects expression of pre- and postsynaptic proteins, and Malat1 is translated to produce a micropeptide regulated by synaptic activity, thus providing insight into a novel mechanism by which Malat1 can affect neuronal maturation and activity.

Abstract

Synaptic function in neurons 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 long noncoding RNA. We found that in differentiating neurons, a portion of Malat1 RNA redistributes to the cytoplasm. Depletion of Malat1 using antisense oligonucleotides (ASOs) stimulates the expression of particular pre- and postsynaptic proteins, implicating Malat1 in their regulation. Neuronal Malat1 is localized in puncta of both axons and dendrites that costain with Staufen1 protein, similar to neuronal RNA granules formed by locally translated mRNAs. Ribosome profiling of cultured mouse cortical neurons identified ribosome footprints within a 5′ region of Malat1 containing short open reading frames. The upstream-most reading frame (M1) of the Malat1 locus was linked to the GFP-coding sequence in mouse embryonic stem 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 wild-type neurons and showed that M1 expression was enhanced by synaptic stimulation with KCl. Our results indicate that Malat1 serves as a cytoplasmic coding RNA in the brain that is both modulated by and modulates synaptic function.