Multiple Copies of microRNA Binding Sites in Long 3′UTR Variants Regulate Axonal Translation

Luba Farberov, Ariel Ionescu, Yazeed Zoabi, Guy Shapira, Amjd Ibraheem, Yosi Azan, Eran Perlson*, Noam Shomron*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Rapid responses to changes within subcellular compartments of highly polarized cells, such as neuron axons, depend on local translation and post-transcriptional regulation. The mechanism by which microRNAs (miRNAs) regulate this process is not 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 demonstrated that the seed match length of the miRNA target-sequence regulates both mRNA stability and protein translation rates. While longer seed matches have an increased inhibitory effect, transcriptome analysis did not reveal differences in seed match length between axonal and somata mRNAs of motor neurons. However, mRNA variants with longer 3′UTR are enriched in axons and contain multiple repeats of specific miRNA target sequences. Finally, 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 match length, regulates the axonal transcriptome.

Original languageEnglish
Article number233
JournalCells
Volume12
Issue number2
DOIs
StatePublished - Jan 2023

Funding

FundersFunder number
CBRN
Edmond J. Safra Center for Bioinformatics at Tel-Aviv University
Kirschman Dvora Eleonora Fund for Parkinson’s Disease studies
Koret-UC Berkeley-Tel Aviv University
Office of Assistant Minister of Defense for Chemical, Biological, Radiological and Nuclear
RADALA Foundation
Research and Innovation Framework Programme
UCSF-Tel Aviv University
EU Joint Programme – Neurodegenerative Disease Research
Foundation Fighting Blindness
Human Frontier Science Program
Yonsei University
Israel Science Foundation3-17160, RGP0026/2020-102
Tel Aviv University
Queensland Brain Institute
Ministry of Science and Technology, Israel
Ministry of Health, State of Israel
Horizon 2020
Ministry of Defense

    Keywords

    • 3′UTR
    • KIF5B
    • RNA localization
    • RNA translation
    • axons
    • miR-129-5p
    • seed

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