EGFR signaling coordinates patterning with cell survival during Drosophila epidermal development
Posted on: 26 September 2018
Preprint posted on 28 August 2018
Article now published in PLOS Biology at http://dx.doi.org/10.1371/journal.pbio.3000027
Why do cells die when they are in the "wrong" place? Preprint shows lack of EGFR signalling, rather than any cell fitness recognition event, is responsible
Selected by Sarah BowlingCategories: developmental biology
Background
Cells that fail to form the correct tissue for their environment are often eliminated by apoptosis. This phenomenon has been observed across model organisms from zebrafish to mice, and is triggered by mutation of signalling pathway genes required for patterning. The phenotype is particularly evident in Drosophila segmentation mutants: mutation of genes that function at different steps of the segmentation cascade to define the Drosophila body plan leads to widespread apoptosis in the compartment where they are normally expressed (Fig. 1).
Fig. 1. Left: Wild-type larvae with normal expression of segment polarity genes (red) have low levels of apoptosis (green). Right: Deletion of pair-end gene fushi-tarazu (ftz) leads to disruption of segment polarity genes (red) and widespread apoptosis (green). Reproduced/ adapted from Crossman et al, 2018 BioRxiv.
What is less clear is why the mispatterned cells are eliminated. A prevailing hypothesis is that a fitness recognition event by surrounding cells leads to their active elimination through cell competition. An alternative, unexplored hypothesis is that mispatterning disrupts signalling pathways required for cell survival. In this preprint, Crossman and colleagues shed light on the mechanisms underlying this phenomenon.
Experiments
Initially the authors demonstrate that cell death occurs in flies with various gene mutations involved in segmentation, and pick fushi-tarazu (ftz) mutants (Fig. 1) for further investigation of the phenomenon. Using this model the authors show that, consistent with a previous study (Werz et al, 2005), cell death in segmentation mutants occurs through activation of the apoptotic gene hid. This gene is expressed highly in ftz mutant flies, and its disruption rescues the apoptosis phenotype observed in segmentation mutants.
Next the authors screen for upstream mediators of cell death and find that overexpression of the activated EGF receptor reduces cell death in ftz mutants. Further analysis revealed that EGFR target phospho-ERK has altered activity in ftz embryos compared to wild-types. Specifically, while phospho-ERK activity is sustained at a high level along the anterior-posterior axis of wild-type larvae with small peaks at segment boundaries, in ftz mutants pERK activity is inconsistent and marked by large “gaps” in signal within segments. Notably, areas of low pERK activity correspond to high levels of cell death in mutant flies. This further supports a role for EGFR in cell survival, together with the finding that deletion of EGFR results in widespread hid expression. The authors next identify vein and rho-1 as important ligands involved in EGFR activation. In wild-type embryos, vein and rho-1 are expressed at the boundaries of segments. In ftz embryos, vein and rho-1 fail to form these patterns, in agreement with the disrupted phospho-ERK activity.
Finally, the authors use multiview single plane illumination microscopy (mSPIM) to record total apoptotic cells in whole wild-type embryos. Mapping apoptotic events and position within the segment by staining for cleaved death caspase-1 leads to the emergence of a pattern where apoptosis becomes more frequent as distance from segment borders (the EGF-ligand sources) grows. This finding suggests that in normal development, exposure to EGFR signalling dictates cell survival and is possibly involved in maintaining cell number and therefore compartment size.
Conclusions and thoughts
Through a series of elegant genetics experiments and image analysis, the authors show that death of mispatterned cells in Drosophila segmentation mutants arises from disrupted EGFR signalling patterns. In addition, the data indicate that insufficient exposure to EGFR signalling could be a trigger of cell death in wild-type larvae.
Importantly, the preprint leads to the intriguing suggestion that as well as dictating compartment boundaries, segmentation genes could also control compartment size through tight regulation of EGFR signalling. This builds on previous studies implicating EGFR signalling in cell number regulation (Urban et al, 2004; Bergmann et al, 2002; Gioboa and Lehmann, 2006; Parker, 2006), and extends the findings by implicating the pathway in size control of whole segments in the developing larvae. This sizing mechanism, where a limited source of a growth factor supports survival of only a subset of produced cells, is reminiscent of that described for developing neurons in mice, where cells are massively overproduced and compete for limited levels of nerve growth factor (Raff, 1992). Together, the findings suggest that tight regulation of cell death, as much as proliferation, enables the establishment of normal body and organ size during development.
Questions
Death of mispatterned cells is also seen in systems with less distinct signalling compartments. For example, in mice, deletion of APC in the developing neural crest results in massive apoptosis (Hasegawa et al, 2002). Given the system differences, do the authors think that similar mechanisms are responsible in this context?
The authors make the interesting observation that apoptosis is triggered at embryonic stage 11, long after ftz should have fulfilled its function in segmentation and after the cessation of proliferation. It would be really interesting to know how this time-dependent sensitisation to low EGFR signalling is orchestrated – are there any contender mechanisms?
doi: https://doi.org/10.1242/prelights.4947
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