Crossman, SH; (2018) Quality Control in Developing Epithelia. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

In the fruit-fly Drosophila melanogaster, extensive apoptosis is observed throughout the embryonic epidermis upon the mutation of many essential patterning genes. The molecular basis of cell elimination in this context is poorly understood, although previous studies have suggested the existence of a cell-autonomous quality control mechanism, which detects cells unable to adopt an appropriate terminal fate and removes them through apoptosis. This hypothetical system is thought to protect against patterning errors in order to preserve the integrity of the developing epidermis. To identify factors required for apoptosis in mis-patterned cells, I performed a targeted genetic screen, which identified a potential role for the EGFR signalling pathway in this process. Excess EGFR signalling was shown to rescue the cell death phenotype of the archetypal patterning mutant fushi tarazu (ftz), whilst EGFR null alleles triggered extensive epidermal apoptosis. Upon further experimentation, I was able to show that patterning mutant embryos fail to express the major EGFR activating ligands in the correct spatial pattern. This causes local troughs in EGFR signalling, which trigger transcriptional upregulation of the pro-apoptotic gene hid and subsequent cell death. These results argue against a cell-autonomous mechanism of cell elimination in mis-patterned embryos and instead suggest that the tissue-wide landscape of EGFR activity is responsible for coordinating cell fate and cell survival in the embryonic epidermis. Building on these observations, I have been able to show that the EGFR pathway also regulates apoptosis during normal development, where it specifies the maximum dimensions of embryonic segments. Taken together, these findings provide a novel link between early patterning events, cell viability and compartment size in the developing Drosophila embryo.

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