Hosts: Kees Weijer & Rastko Sknepnek

Venue: MSI Small Lecture Theatre, SLS

Abstract: During gastrulation, coordinated cell behaviours sculpt the vertebrate body plan. We previously quantified the tissue flows emerging from these multicellular dynamics in terms of dynamic attractors and repellers (M. S. et al. PNAS, 2020). We also linked cell behaviours to self-organized tissue flows using a theoretical model whereby gastrulation results from a mechanosensitive-myosin instability (M. S. et al. Sci. Adv., 2023). Experiments and modelling determined that the attractor's shape depends on initial myosin patterns and cell ingression (M. C. et al. Sci. Adv., 2023). We now focus on deciphering the mechanistic origins of morphogenetic repellers. By extending our model, we find that one repeller arises from the tug-of-war between the embryo and the extraembryonic tissue, while the second repeller self-organizes solely from the convergent extension of the mesoderm. To test these predictions, we developed ex-ovo cultures, enabling the manipulation of the embryonic geometry in parallel with live imaging and flow quantification. By applying mechanical and chemical interventions inspired by our model, we were able to eliminate both repellers independently in chick embryos. Overall, our integrated modelling and perturbation approach reveals how coordinated cell behaviours sculpt a biomechanical landscape of attractors/repellers guiding avian gastrulation, elucidating the role of extraembryonic epiboly forces, embryonic apical constriction, ingression, and mechanosensitive myosin activity. 
 

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Host: Prof Simon Arthur

Abstract  

The KEAP1-NRF2 pathway is a cytoprotective pathway which allows cells to respond and adapt to a broad range of toxic chemical stimuli. KEAP1 is an E3 ubiquitin ligase adapter which, under basal non-stressed conditions, targets the transcription factor NRF2 for ubiquitination and proteasome-dependent degradation. The KEAP1 protein is equipped with a number of highly reactive cysteine-based sensors which allow it to directly sense and bind to electrophiles and oxidants. The triggering of these sensors inactivates KEAP1, resulting in nuclear accumulation of NRF2, and the transcriptional upregulation of a network of genes encoding cytoprotective proteins.

In response to irreparable cellular damage, I recently found that activation of NRF2 results in the upregulation of a unique secretory transcriptional program, which I named the NRF2-Induced Secretory Phenotype, or NISP. Genetic mouse models revealed that the function of the NISP is to recruit immune effector cells, including CCR2+ classical monocytes, to the site of tissue damage so that the irreparably damaged cells can be safely removed through phagocytosis or efferocytosis. This model represents the termination of the oxidative stress response under conditions in which the cellular damage cannot be repaired, as otherwise, the maintenance of damage cells in situ would be deleterious for organismal survival due to the potentially cancerous nature of the damaged cells.

In this seminar, I will introduce the NRF2-NISP-Immune surveillance model, and discuss some of the implications of this model in relation to cancer development, anti-cancer drug strategies and anti-viral responses.