RNA-RNA interactions coordinate GABA metabolism and signaling

Abstract

How functionally related genes are coordinately expressed within a given cell type remains poorly understood. Here we reveal that the 3'UTR, beyond binding RNA-binding proteins and microRNAs, mediates heterotypic RNA-RNA interactions that confer cell type-specific gene expression, and demonstrate that this function is essential for GABAergic signaling in Drosophila. We show the vesicular GABA transporter VGAT is transcribed pan-neuronally but its translation is repressed in non-GABAergic neurons by miR-7 through three conserved 3'UTR sites. We identify a GABAergic neuron-specific lncRNA, GABA UnLocker (Gul), with sequences complementary to all three VGAT miR-7 sites that derepresses VGAT translation. Gul is co-expressed with the adjacent Gad1 gene, which produces GABA, in all GABAergic neurons, such that a single GABAergic neuron-specific transcriptional input instructs both GABA synthesis and, via Gul, the transporter for GABA release. Gul also targets other mRNAs in GABA metabolism, suggesting that it coordinates GABAergic gene expression through 3'UTR RNA-RNA interactions.