Signaling dynamics and pattern formation: modeling, imaging and manipulating cell fate specification – ModelPattern

How shapes and patterns form during the development of multicellular organisms is a long-standing question in life sciences. This question is of fundamental importance since function (physiology) is intimately linked to structure and since the ontogeny of shapes and patterns is rooted into the history of life (evolution). Here, we propose to revisit a classic example of developmental patterning that first defines stripes within a two-dimensional field of cells and second resolves these stripes into singled-out dots. These stripes correspond to groups of cells expressing the proneural genes in the Drosophila notum epithelium that will give rise to the dorsal thorax in adult fruit flies; dots correspond to the regularly space sensory bristles, hence producing a pattern of rows. Using new fluorescent reporters generated through genome engineering, we have begun to describe the dynamics of this patterning. Based on these observations, we have formulated a novel and simple mathematical model that strongly suggests that a single mechanism based on self-organization and involving cell-cell interactions mediated by Delta-Notch signaling regulates both stripe patterning and selection of regularly spaced bristle precursor cells within these stripes.

By combining mathematical modeling (to produce simulations and explore the constraints of the model), genome engineering and optogenetics (to produce new reporters and controlled perturbations), quantitative live imaging and 2-photon light sheet imaging (to quantify the dynamics of the underlying processes), we will quantify the “inputs” to patterning (i.e. a gradient of the Notch ligand Delta), and the dynamics of downstream cell-cell interactions and explicitly relate them to their molecular and cellular basis. Moreover, by comparing with other species and developmental contexts, we will shed light on how different contributors to patterning can be modulated or “repurposed” during evolution. This analysis will provide an integrated, quantitative description that explicitly connects the molecular scale, cellular dynamics, and the logic of developmental patterning.

The strengths of our project lie in the simplicity of this well characterized developmental system, the power of combining mathematical modeling, fly genetics, genome engineering, live imaging, recent advances in microscopy and optogenetics, and above all on the complementary expertise of the two PIs and on their proven ability to collaborate.