Changes in protein expression underlie cell activity. One way to control protein levels is through post-transcriptional regulation of mRNAs, which can be localised to sub-cellular domains. This conserved mechanism for the spatial regulation of gene expression enables cells to target protein function in space and time and is especially relevant in the patterning of embryonic axes, formation of neuronal networks and movement of cells. Failure to control localised translation is implicated in a number of human diseases, including Fragile X Syndrome, schizophrenia, spinal muscular atrophy and cancer.
To understand how the fundamental processes of localised translation and egg activation are achieved, we use Drosophila as a model system since imaging, biochemistry and genetic approaches can be readily combined to examine molecular mechanisms. Drosophila research has identified thousands of genes with human homologues and has provided key insights into developmental pathways, oncology, neurobiology and immunology. Our use of the egg chamber and the early embryo has the added experimental benefits of: being an in vivo developing system; allowing for a controllable switch at egg activation; ease of physical manipulation; and providing ample material for experimentation.
Current research topics include:
Elucidating the mechanism of the first round of mRNA translation
This project 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.
Establishing the mechanism of the calcium wave at egg activation
Egg activation is a conserved process required to prepare an egg for fertilisation and embryogenesis. In all animals, egg activation is associated with at least one transient increase in cytosolic calcium concentration, a “calcium wave”. The calcium wave is required for resumption of the cell cycle, reconfiguring of the cytoskeleton, cortical granule exocytosis and translation of maternal transcripts. This project aims to characterise in detail the mechanisms that drive initiation and propagation of calcium waves in eggs at activation. Drosophila is an attractive model of choice for this due to its genetic tractability, imaging options and ease of manipulation. To achieve our goals, we use methods already successfully applied in our laboratory, including in vivo advanced imaging of genetically encoded calcium indicators, genetic analysis of key factors, pharmacological disruption and physical micro-manipulation.
Testing the function of calcium in programmed cell death
To coordinate decisions, cells read and respond to both internal and external cues. Especially during development, cell decisions must be highly regulated in both space and time. This regulation ensures correct outcomes occur. These include cell contraction leading to tissue morphogenesis and programmed cell death to clear cells once their role has been fulfilled.
The main goal of this project is to elucidate the molecular mechanisms underlying coordinated cell decisions in development. We use the rapid transfer of cytoplasm and programmed death of Drosophila nurse cells as our model system. Previous work shows these processes require an intact actomyosin network and calcium signalling.
Key Publications
Derrick C. J. & Weil T. T. Translational control of gurken mRNA in Drosophila development. Cell Cycle, Vol. 16 , Iss 1, 23-32 (2017).
Davidson A., Parton R.M., Rabouille C., Weil T.T., Davis I.: Localized Translation of gurken/TGF-α mRNA during Axis Specification Is Controlled by Access to Orb/CPEB on Processing Bodies. Cell Reports; 14(10):2451-62. Mar 15 (2016).
York-Andersen A.H., Parton R.M., Bi C.J., Bromley C.L., Davis I., Weil T.T.: A single and rapid calcium wave at egg activation in Drosophila. Biology Open; 4(4):553-60. Mar. (2015).
Weil T. T., Parton R. M., Herpers B., Soetaert J., Veenendaal T., Xanthakis D., Dobbie I., Halstead J. M., Hayashi R., Rabouille C., Davis I.: Drosophila patterning is established by differential association of mRNA with P bodies. Nat Cell Biol.; 14(12) 1305-13 Dec. (2012).
Weil T. T., Xanthakis D, Parton R., Dobbie I., Rabouille C., Gavis E. R., Davis I.: Distinguishing direct from indirect roles for bicoid mRNA localization factors. Development; 137: 169-76. Jan. (2010).