On January 15th we have a guest speaker. Olivier Pertz from the University of Bern will talk about his work on Decoding and Re-encoding MAPK Fate Decision Signaling.
Date: January 15th
Time: 4 p.m.
Venue: IRI Life Sciences,
Humboldt-Universität zu Berlin,
Philippstr. 13, Michaelis Building (No 18),
Maud Menten Hall (3rd Floor)
https://goo.gl/maps/9LUWXKXj6pv
Decoding and Re-encoding MAPK Fate Decision Signaling
Olivier Pertz, Institute of Cell Biology, University of Bern
Cells dynamically sense and respond to ever changing external stimuli through sophisticated signaling networks. Accordingly, signaling dynamics rather than steady states control fate decisions. For many signaling pathways, heterogeneous dynamic signaling states occur within distinct cells, explaining fate variability observed within a cell population. Measuring single cell signaling dynamics is therefore key to understand how cellular responses correlate with specific cell fate decisions. Here, we combine biosensor imaging, microfluidics, optogenetics and mathematical modelling to map how different MAPK signalling network circuitries fine tune ERK activity dynamics at the single cell level.
In PC-12 cells, a classic model for fate determination, we observe that different growth factors (GFs) wire the MAPK pathway differently to modify the population distribution of
transient/sustained ERK states that are known to induce proliferation/differentiation fates.
EGF only induces transient ERK states; NGF results in a mix of transient/sustained ERK states, with a sharp increase of the latter at high GF input; FGF gradually modifies the population distribution of transient/sustained ERK states in response to augmenting GF input. The latter feature might be consistent with FGF-dependent fate determination in developmental morphogen gradients. Thus, the distinctive GFs wire the MAPK network differently to control the population distributions of transient/sustained ERK states, and fates. Temporal perturbations applied using microfluidics and optogenetics provide highly informative novel signalling states that allow us to infer the feedback structure inherent to the different networks. Ultimately, this allows us to reprogram fate decisions at will by evoking synthetic dynamic signalling states using temporal perturbations.
I will also discuss on another fate determination system in which MCF10A breast epithelial
cells constantly senses the state of the cell collective, and reacts by spatially tuning survival and proliferation fates to ensuring a critical cell density necessary for proper barrier function. Here we observe two single-cell ERK signalling modes that consist either of stochastic pulses (in presence of GFs), or of co-ordinated ERK waves across multiple cell layers that originate around apoptotic extruding cells (in absence of GFs or in presence of cytotoxic agents). We show that such ERK activity pulses provide a survival signal for about 3 hours allowing to constantly fine tune fate determination during this epithelial homeostasis process. A further degree of spatio-temporal signalling complexity is observed when these cells are grown as 3D epithelial spheroids which can then explain morphogenetic processes such as lumen formation.
Together, these results showcase the rich variety of information processing/transfer enabled by the MAPK/ERK pathway to warrant robust regulation fate decisions at biologically relevant time/length scales.