JNK_Life.Death · Role of dynamic JNK signalling in balancing cell removal and renewal in a stressed epithelium
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2023-01-01 → 2024-12-31
- EU contribution
- €212,934
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Role of dynamic JNK signalling in balancing cell removal and renewal in a stressed epithelium
The development of functional tissues relies on the fine balance between cell death and cell division. Little is known about how tissue size and cell numbers are maintained in stress situations when additional proliferation is needed to compensate for cell loss. The c-Jun N-terminal kinases (JNK) signalling pathway is a stress pathway that has been proposed to trigger not only cell death but also cell survival and proliferation. To decipher the regulatory events that control these diverse responses, we have set out to characterise the spatial-temporal dynamics of cell fate (proliferation, cell death, cell cycle arrest and migration) upon JNK activation. We optogenetically activate signalling in a subset of cells by expressing either a constitutively active form of the JNK Kinase hemipterous (hep). Then, we reconstruct the cell-autonomous and non-autonomous response to stress signalling. The response is very fast: we observe cell death and cell cycle arrest within two hours of Hep activation. However, the response lasts for an extended time, with a population expressing low JNK levels being observed 18 hours after the light pulse. We reconstructed the pattern of gene expression in time and space, using both biased and unbiased approaches. First, we used the Hybridization Chain Reaction to visualise the expression of genes known to be regulated by JNK signalling, such as Wg/Wnt and Dpp/BMP. Finally, we performed bulk RNA sequencing to identify the genes that could potentially account for the varied effect of JNK signalling activation. We discovered that under temporary and mild stress levels, there is no significant upregulation of morphogens/growth factors but instead of their modulators: glypicans. In the absence of glypicans, the replacement of lost cells is impaired. We hope that our results will guide further studies of more complex tissues of direct biomedical relevance.
Data: CORDIS, © European Union
Project objective
Tissue homeostasis requires a tight maintenance of cell number. Little is known about how tissue size and cell numbers are maintained in stress situations, when additional proliferation is needed to compensate for cell loss. I propose to study the homeostatic response to stress in a tissue (Drosophila wing primordia) in which Ribosomal Proteins-deficiency causes extensive apoptosis compensated by extra proliferation. How are these two responses balanced to ensure the emergence of a normal adult organism? JNK signalling is a strong candidate to mediate both apoptosis and proliferation responses. I propose to decipher the regulatory events that control this two-faced response, and to identify the proliferative pathways activated by JNK. Using the latest tools of genome engineering and live imaging, I aim at unravelling the spatio-temporal dynamics of JNK signalling and the downstream activation of cell death or division. Next, I will use a candidate gene and an unbiased approaches to uncover the transcriptional programs that correlate with apoptosis and proliferation. Lastly, I will verify the relevance of the identified candidates and investigate their spatial-temporal activity upon JNK activation. The results will be key to reaching the next stage of understanding the role of JNK in orchestrating the concerted replacement of lost cells that ultimately results in functional epithelia. Uncovering this logic in a relatively simple epithelium will hopefully guide further studies in more complex tissues of direct biomedical relevance.
Original text from CORDIS.
Participants
- THE FRANCIS CRICK INSTITUTE LIMITED · LondonCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union