Cell-fate transitions in dynamic signalling environments

Schematics of vulval cell-fate determination and the project idea. (A) Cell-fate patterning of the six vulval precursor cells in C. elegans through the combined action of EGF and Notch/Delta signaling. An organizer cell, called anchor cell emits an EGF signal that activates the ERK kinase after signal transduction. Lateral inhibition is mediated through Notch/Delta signaling to specify three…

Project description

The signalling pathway dynamics regulating developmental cell-fate decisions are immensely complex, but, at the same time, stem cells typically only decide between a limited repertoire of fates. This suggests that simple, intuitive regulatory biophysical principles may successfully summarize pathway complexity. The objective of this project is to establish and quantitatively test such principles, using the egg-laying organ of the nematode C. elegans as a model system. To do so, we combine: (i) Controlled perturbations of in-vivo signalling dynamics using microfluidics (ii) Large-scale 4D live imaging to capture cell-fate transformations in response to perturbed signaling (iii) Parsimonious mathematical modelling of the underlying cell-fate acquisition dynamics. This combination allows direct quantitative in-vivo measurements of the relationship between the dynamics of multiple signalling pathways and the specification of cell fates. 

References:

Real-time ERK Biosensor: de la Cova, C., Townley, R., Regot, S., & Greenwald, I. (2017). A Real-Time Biosensor for ERK Activity Reveals Signaling Dynamics during C. elegans Cell Fate Specification. Developmental Cell, 42(5),542-553.e4.  https://doi.org/10.1016/j.devcel.2017.07.014

Mathematical modeling of vulval cell-fate specification: Corson, F., & Siggia, E. D. (2017). Gene-free methodology for cell fate dynamics during development. ELife, 6, 1–25. https://doi.org/10.7554/eLife.30743