Mechanistic links between morphogenesis and differentiation

As cells build the body, they use information from localised secreted signals to guide differentiation and morphogenesis.

It is often assumed there is unidirectional flow of information from these biochemical signals to the resulting morphological changes, but this 'linear' model cannot explain how development is orchestrated with such remarkable reproducibility.

We have found that changes in epithelial structure provide a previously underappreciated source of information that feeds back into differentiation decisions by modulating biochemical signalling.

Using mouse gastrulation as a paradigm we have identified candidate molecular mechanisms that mediate this feedback: 1) A cadherin-mediated community effect that dampens anti-neural signals to synchronise neural differentiation 2) a cell-clustering process that amplifies juxtacrine pro-mesoderm signalling to coordinate differentiation across collectives of cells.

We propose that these two interlinked mechanisms coordinate distinct sources of information across different time scales.

We will test this in vitro and in vivo using a unique toolkit based on molecular and biophysical manipulation of epithelial structure, mosaic analysis, and custom-developed quantitative image analysis software.

Generalisable principles emerging from this work will help resolve the currently unpredictable relationship between "signalling-input" and "differentiation-output" to give us better control over in-vitro differentiation, organoid formation, tissue repair, and tumorogenesis.