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Rotation project: Testing the function of calcium in programmed cell death (Timothy Weil)

Testing the function of calcium in programmed cell deathTesting the function of calcium in programmed cell death

Supervisor: Dr Timothy Weil

Project Summary:

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.

Our experiments testing these and other factors suggest that prostaglandin synthesis inhibition results in aberrant calcium signalling and that the onset of these processes are asynchronous. Building on these exciting findings, this project aims to further interrogate the mechanisms involved through in vivo live cell imaging, genetic manipulation and mathematical modelling.

This work is of broad interest due to the prevalence of calcium and prostaglandins as factors in coordinating cellular change which are implicated in many basic cellular processes and human diseases.

Long-term project outlook (PhD):

A PhD project following this rotation would aim to elucidate how cells respond to external and developmental stimuli. Of particular interest is how primary signals are amplified by second messengers to regulate the precise response of the cell. Prostaglandins and calcium are prime second messenger candidates, responsible for the coordination of several cellular responses such as cytoskeletal rearrangement and cell death.

The overall goal of this project is to establish the full mechanistic understanding of prostaglandins and calcium-mediated change at both the individual and multi-cellular level. Key initial experiments will be the targeted mutagenesis of identified candidates with CRISPR/Cas9, the visualisation of calcium and actin in these mutant backgrounds and mosaic analysis of mutant nurse cells. These techniques fit well with the current research agenda of the Weil Lab.

References:

Drosophila Pxt: a cyclooxygenase-like facilitator of follicle maturation.

Tootle TL & Spradling AC

Development. (2008) Mar;135(5):839-47.

 

Drosophila quail, a villin-related protein, bundles actin filaments in apoptotic nurse cells.

Matova N, Mahajan-Miklos S, Mooseker MS, Cooley L.

Development. (1999) Dec;126(24):5645-57.

 

Preparing individual Drosophila egg chambers for live imaging.

Weil TT, Parton RM, Davis I.

J Vis Exp. (2012) Feb 27;(60).