Elucidating the mechanism of the first round of mRNA translation
Supervisor: Dr Timothy Weil
This projects aims to understand the molecular mechanisms leading to the first round of mRNA translation. This is a fundamental question in biology since controlling the initiation of translation is essential in all cells.
To explore this, we utilise the oocyte-to-embryo transition in Drosophila which enables research in an in vivo context, an approach that has been under-investigated. This project uses genetic and chemical manipulation in conjunction with advanced imaging to monitor the first round of translation in real-time.
We have successfully applied a novel RNA biosensor (TRICK system) for imaging the first round of mRNA translation in vivo and have novel preliminary data showing the initiation of translation is considerably faster than previously suggested. We also have exciting data linking the dispersion of Processing bodies, conserved cytoplasmic regions of mRNA regulation, and intracellular calcium levels to the activation of translation.
Translational regulation is crucial and misregulation of mRNA function has a role in developmental defects as well as neurodegenerative and genetic diseases. Therefore, the results of this project are likely to shed considerable light on the basic processes underpinning both cell biology and disease.
Long-term project outlook (PhD):
Building on this rotation, a PhD project would aim to resolve the mechanism of translational activation. Using in vivo techniques that have been established in the Weil Lab, this project would offer a unique and unparalleled approach at resolving the fundamental question of how cells regulate protein production spatially and temporally.
First experiments would include assaying translation with the TRICK system in different genetic backgrounds and under specific experimental conditions. A likely approach would be to identify the proteins associated with the regulated mRNA before and after translational activation in wild type and mutant mRNAs through biochemistry (CLIP). These data will identify key proteins that mediate changes in translational activation to then be observed in vivo. This is a particularly appealing project as the initiation of protein synthesis allows cells to orchestrate changes with exquisite sub-cellular and temporal precision thus making it a cornerstone of cell biology.
An RNA biosensor for imaging the first round of translation from single cells to living animals.
Halstead JM, Lionnet T, Wilbertz JH, Wippich F, Ephrussi A, Singer RH, Chao JA.
Science. 2015 Mar 20;347(6228):1367-671.
Drosophila patterning is established by differential association of mRNAs with P bodies.
Weil TT, Parton RM, Herpers B, Soetaert J, Veenendaal T, Xanthakis D, Dobbie IM, Halstead JM, Hayashi R, Rabouille C, Davis I.
Nat Cell Biol. 2012 Dec;14(12):1305-13.
Post-transcriptional regulation of embryogenesis.
F1000Prime Rep. 2015 Mar 3;7:31.