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Multiple copies of microRNA binding sites in long 3’UTR variants regulate axonal gene expression

ABSTRACT: Rapid responses to changes over space and time within highly polarized cells, such as motor neurons, depend on local translation and post-transcriptional regulation in distinct subcellular compartments such as axons. MicroRNAs (miRNAs) can regulate this process in a mechanism that is not yet fully understood. Here, using live cell imaging and RNA sequencing analysis, we demonstrated how miRNAs can differentially control hundreds of transcripts at the subcellular level. We confirmed that the length of the miRNA target-sequence regulates both mRNA stability and protein translation rates; longer seed regions have an increased inhibitory effect. Interestingly, transcriptome analysis of the motor neuron subcellular compartments did not reveal any differences in seed length between axonal and somata mRNAs. However, we recognized that long 3’UTRmRNA variants are enriched in axons and contain more sequence repeats, particularly for binding a few specific miRNA. Finally, as proof of concept, we demonstrated that the long 3’UTR mRNA variant of the motor protein kif5b is enriched explicitly in motor neuron axons and contains multiple sequence repeats for binding miR-129-5p. This subsequently results in the differential post-transcriptional regulation of kif5b and its synthesis in axons. Thus, we suggest that the number of miRNA binding sites at the 3’UTR of the mRNA, rather than the miRNA seed length, regulates the axonal transcriptome. These new insights clarify how globally expressed miRNA can adaptively interact with their targets at the subcellular level, while possibly driving multiple cellular functions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE188770 | GEO | 2023/01/25

REPOSITORIES: GEO

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