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Humboldt-Universität zu Berlin | IRI Life Sciences | Scientific Events | Colloquium | Heterogeneity | IRI-Colloquium NEW SERIES on Heterogeneity in Biological Systems: Olivier Pertz

IRI-Colloquium NEW SERIES on Heterogeneity in Biological Systems: Olivier Pertz

When Jan 15, 2020 from 04:00 PM to 05:00 PM (Europe/Vienna / UTC100) iCal
Where IRI Life Sciences, Philippstr. 13, Building 18, 3rd Floor, Room 410
Contact Name
Contact Phone 030209347904

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Speaker: Olivier Pertz (University of Bern)

Title: Decoding and Re-encoding MAPK Fate Decision Signaling“. 

 

Abstract

 

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.