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Mechanism and functional impact of ultra-long 3’ UTRs in the Drosophila nervous system

Project description

Role of ultra-long 3’ UTRs in neuronal functions

The recently discovered striking process of drastic lengthening of the 3’ untranslated region (3’ UTR) of hundreds of genes occurs in neurons. The function of the resulting ultra-long 3’ UTRs is unknown. It is essential to study regulatory processes and define the function of these novel 3’ UTRs, to better understand the role of RNA deregulation in neurological diseases. The EU-funded Neuro-UTR project investigates regulation and function of ultra-long 3’ UTRs in the Drosophila nervous system. Research is based on the hypothesis that mRNAs carrying ultra-long 3’ UTRs enable critical communication between transcription regulation and synaptic function. Neuro-UTR will define the mechanism of the co-transcriptional processes that give rise to ultra-long 3’ UTRs. The project will analyse the role of ultra-long 3’ UTRs in memory, ageing and disease.

Objective

Neurons employ cell-specific gene regulatory mechanisms. One particularly striking process is the recently discovered, drastic lengthening of the 3’ untranslated region (3’ UTR) of hundreds of genes, which occurs in neurons from flies to humans. The function of the resulting ultra-long 3’ UTRs is unknown. RNA deregulation plays a central role in neurological diseases; to understand underlying causes, it is essential to study regulatory processes and define the function of these novel 3’ UTRs.
In Drosophila, the neuronal RNA-binding protein ELAV is the main effector of nervous system specific 3’ UTR extension. ELAV’s association with the promoter region of its target genes is required for synthesis of alternative, ultra-long 3’ UTRs. The mechanistic framework of this novel and exciting link between transcription initiation and alternative 3’ end processing is not understood yet.
We hypothesise that mRNAs carrying ultra-long 3’ UTRs create an important communication avenue between transcription regulation and synaptic function. In this proposal, we will study the regulation of ELAV-mediated 3’ UTR extension in a Drosophila model. First, we will provide mechanistic insight into the co-transcriptional processes that give rise to ultra-long 3’ UTRs. Employing genomics, proteomics and biochemistry, we will study the recruitment of ELAV at gene promoters and to nascent mRNA. Second, we will follow the journey of extended mRNAs from their site of synthesis to their destination using imaging, proteomics, and functional genetics. Finally, based on our unpublished results that 3’ UTR plasticity impacts neuronal function, we will analyse the role of ultra-long 3’ UTRs in memory, aging and disease.
Our study will integrate the molecular mechanisms that govern biogenesis and function of ultra-long 3’ UTRs, from nucleus to synapse, in an animal model. The results of this research will create a major impact on our understanding of neuronal gene regulation in health and disease.

Host institution

MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV
Net EU contribution
€ 1 497 500,00
Address
HOFGARTENSTRASSE 8
80539 Munchen
Germany

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Region
Bayern Oberbayern München, Kreisfreie Stadt
Activity type
Research Organisations
Links
Total cost
€ 1 497 500,00

Beneficiaries (1)