Completed Genetics & Molecular Biology Brain & Nervous System

The mechanism of mRNA transport and localised translation during axis specification and synaptic plasticity.

Funder Wellcome Charity-funded
Recipient organisation University of Oxford
Funding £3.1M
Period Jul 2012 — Jun 2018

In plain English

AI plain-English summary

Inside a fruit fly egg, a single molecule of messenger RNA hitches a ride to a specific spot, ensuring that the future head and tail of the embryo form in the right places. This same process—shuttling genetic instructions to precise locations within a cell—also governs how neurons strengthen their connections during learning and memory. The problem is that the molecular machinery behind this transport and localised translation remains poorly understood, especially in the context of brain function. This project will dissect how a protein called Syncrip, which the team has already shown to be essential for localising mRNA in both fly eggs and nerve cells, controls the translation of key transcripts at synapses. By identifying the full set of RNA molecules that hitch a ride to the neuromuscular junction, and by working out how Syncrip and its partner proteins regulate them, the researchers aim to map a fundamental mechanism of cellular organisation. This is fundamental science. A deeper understanding of how neurons locally control protein production could, in the long term, reveal why this process breaks down in neurodegenerative diseases such as Alzheimer’s, where synaptic dysfunction is an early hallmark.

View original technical description
Intracellular transport of mRNA and its localised translation are common and efficient mechanisms of restricting protein distribution during axis specification in oocytes. They are important for local regulation at the periphery of neurons, during long term memory, synaptic plasticity and are implicated in neurodegenerative diseases. We have discovered conserved trans-acting proteins that bind to the gurken (TGF-alpha) mRNA localisation signal and are required for its localisation and translati onal regulation during Drosophila oocyte axis specification. These include Syncrip, which is conserved in mammals and is complexes with transcripts at hippocampal dendrites. We have shown that Syncrip plays a central role in regulating the translation of localised transcripts, including discs large (PSD-95 in mammals) in neuromuscular synapses. We will use a combination of in vivo and in vitro approaches to characterize the roles of these factors in gurken mRNA localisation and translational reg ulation. We will then elucidate the equivalent functions of Syncrip and its partner trans-acting factors and downstream targets in the neuromuscular junction during synaptic plasticity. Finally, we will search for new transcripts that are localised at the neuromuscular synapse and investigate their mechanism of localisation and function in assembling and regulating the synapse.

View the original record at the funder ↗

Researchers

Ilan Davis (EPMC Awardee)

Related Research

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Original classification

Senior Research Fellowship Basic Renewal

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