MRC National Institute for Medical Research, London
Science for Health
This project is now closed
Uncovering the pathway that recognises misbehaving cells during development
Project supervisor: Jean-Paul Vincent (Developmental Biology)
Embryonic development is an amazingly reliable process. Most embryos give rise to fully patterned organisms with great accuracy. One process that contributes to such accuracy is the elimination of mispecified or defective cells during development. Such elimination is evident in patterning mutants, where cell death is often observed. For example, as shown in the figure, extensive apoptosis is seen fushi tarazu (ftz) mutants of Drosophila. Importantly, ftz is not required for cell survival per se. Indeed, it can be knocked down from cultured cells without deleterious effect. However it is likely that the absence of Ftz during development will cause many cells to express a non-sense combination of developmental regulators. We predict that there is machinery that detects such non-sense and triggers apoptosis as a result. We propose to take advantage of the power of Drosophila genetics to identify components of this hypothetical machinery.
We already know that hid, a key proapoptotic gene, is transcriptionaly upregulated in ftz (and other developmental) mutants. Moreover, Hid is required for apoptosis to take place in ftz mutants. Therefore, we can reduce our aim to the identification of genes that are required for hid upregulation in developmental mutants. To this end, we will first devise a reporter of hid transcription (using genomic engineering and/or BAC recombineering). We will then use a deficiency collection (comprising about 1000 lines that collectively uncover about 90% of the genome) to screen for genes that are required for upregulation of the hid reporter in ftz mutants.
Once such genes are identified, we will ask if they encode general components of apoptosis or whether they are specifically required for the elimination of mis-specified cells. We hope to decipher how the latter contribute to the recognition of mis-specified cells and possibly uncover a novel mechanism of quality control within tissues.
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Apoptosis in a developmental mutant of Drosophila ftz mutant embryos lack the determinants required for specification of every other segments. In the unnaffected segments, engrailed (in green) is normally expressed. In the segments where Ftz normally acts, engrailed is no longer activated and instead, most cell undergo apoptosis, as detected with an antibody that recognises activated Caspase (in red).
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