Apoptosis is a form of cell death that eliminates excessive or mis-specified cells by a caspase-dependent program. Although the machinery involved in the
apoptotic process is relatively well understood, in many instances, the signals instructing cells to initiate this program remain poorly understood. In Drosophila
crumbs mutant embryos, many cells of the epidermis fail to establish apico-basal
polarity and undergo apoptosis as a result. Therefore crumbs embryos can be used
as a model system to investigate how loss of epithelial integrity leads to apoptosis.
As a first step, I have mapped the spatial and temporal pattern of cell death in the
epidermis of crumbs embryos. A strip of 5-10 cells at the dorsal margin survive
and give rise to the crumbs of cuticle that characterise the crumbs mutant
phenotype at the end of embryogenesis. On the ventral and lateral sides, most
cells undergo apoptosis, although the initial pattern of caspase activation has a
clear segmental aspect, anticipated by the segmental expression of the proapoptotic
gene reaper. Genetic evidence shows that reaper is indeed required for
apoptosis in the trunk epidermis of crumbs embryos. The initial question can
therefore be reduced to how does loss of cell polarity lead to activation of reaper
expression. In order to address this question I obtained genome-wide expression
data from crumbs mutant and wild type embryos at three key stages, 10, 11, and
12 of development (apoptosis begins at stage 11 in crumbs mutants). Among the
upregulated genes, I have identified the transcriptional signature of the JNK
signalling pathway. Functional tests have shown that this pathway is indeed
required for the activation of reaper (and apoptosis) in the ventro-lateral
epidermis of crumbs mutants. Additional work has enabled me to further
characterise the links between epithelial integrity, JNK and apoptosis