Description du sujet de thèse

The objective of this project is to provide a quantitative and mechanistic understanding of how graded signalling inputs are converted into switch-like transcriptional outputs in a multicellular context. During development, cells interpret gradients of signalling molecules to generate sharp patterns of gene expression, yet the mechanisms linking input to output remain poorly understood, partly due to intrinsic response heterogeneity.
The project focus on the conversion of a graded FGF-ERK signal into a bimodal ON-OFF transcriptional response of an immediate-early gene (IEG), using ascidian embryos as a model. Their invariant cellular arrangement allows precise identification of cells based on their position. During early neural induction, all eight anterior ectoderm cells contact FGF-expressing mesendoderm, but only two adopt neural fate by activating the IEG Otx. ERK activation levels in ectoderm cells scale with their contact areas with FGF-expressing mesendoderm cells, and this graded input is converted into a bimodal Otx transcriptional response.
The working hypothesis of the project is that this sharp transition results from the opposing actions of ERK-regulated ETS-family transcription factors—Ets1/2 as activator and ERF2 as repressor—competing for the same regulatory DNA sites. We will explore several aspects of this regulatory configuration that potentially contribute to the bimodal transcriptional response: cooperativity; competition between the activator and repressor; multisite phosphorylation; nuclear import-export; protein stability; and sensitivity amplification through cascades of switches. For this project, we collaborate with mathematical modellers and measurements made by the student will be used in the design of a new computational model of this cellular induction.
Given the conservation of ERK signalling and its roles in development and disease, our findings will be broadly relevant to cell signalling, developmental biology, and cancer research.

Contexte de travail

This PhD project will be carried out in partnership between experimental biologists (Laboratory of Developmental Biology in Villefranche-sur-Mer) and computational scientists (Université libre de Bruxelles/Vrije Universiteit Brussel). We will integrate quantitative imaging, molecular biology, and modelling to uncover how graded ERK signals are converted into a bimodal transcriptional response.