RNA transport coupled to local translation presents an efficient means to regulate gene expression in time and space. Recent studies have indicated that this mode of post-transcriptional regulation is used in many different cell types and applied to hundreds to thousands of transcripts. mRNA transport is of particular importance in neurons, where it is involved in processes such as axon guidance and activity-induced synaptic plasticity. Loss of proteins involved in regulating RNA transport have been linked to hereditary mental retardation and dendritic targeting of certain mRNAs has been shown to be crucial for formation of long-term memories. However, which mRNAs are differentially localized in neurons and by what mechanism they are transported remains largely unknown.
Here we propose to investigate this problem using the model organism Drosophila melanogaster, which offers significant experimental advantages, such as little genetic redundancy, powerful tools for loss- and gain-of-function studies and the possibility of visualize living neurons in their natural environment at high resolution. Furthermore, previous work has established that the overall mechanism of RNA transport is conserved from fly to humans. Thus, findings in the fly system are likely to have direct implications for our understanding of the human brain.
We will adapt an established live cell imaging approach to identify mRNAs that are specifically enriched in neuronal processes. Identified transcripts will be characterized in further detail and used to search for RNA-binding proteins that specifically contact their localization elements. Candidate proteins will be tested for a role in mRNA transport using genetics coupled to high resolution imaging. Eventually, proteins regulating mRNA localization will be tested for a physiological role in the brain. Our work should reveal new insights into the cell biology of neurons and have broad implications for neuronal development, plasticity and disease.
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