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Quantitative analysis of the interplay between cellular signaling and cell morphology during development

Final Report Summary - MORPHO-SIGNALING (Quantitative analysis of the interplay between cellular signaling and cell morphology during development)

During development, cells differentiate into well defined patterns through an orchestrated program in space and time. Cell fate determination is coordinated by intercellular signaling and is executed by intracellular genetic circuits. Many of these differentiation processes also involve changes in cell morphology that occur concurrently with the differentiation process. The morphological aspects of differentiation are often treated as a downstream consequence of fate-specific gene expression (e.g. first, cellular states are determined and then regulators of cell morphology are turned on). However, many developmental processes are controlled by a dynamic interplay between cell morphology and cell-cell signaling: Intercellular signals regulate changes in cell morphology while morphological changes affect intercellular signaling and ultimately cell fate decisions. To date, we have large gaps in our understanding of this interplay and we lack a systems level understanding of these processes. At the cellular level, we do not know how intercellular signaling is affected by cell morphology (e.g. how properties of the contact area between cells affect signaling). At the tissue level, we do not understand how to integrate signaling and regulatory processes with tissue morphology and mechanics.

We use the Notch signaling pathway and Notch dependent pattern formation to address these questions. The Notch signaling pathway is the canonical signaling system between neighboring cells across metazoans. It plays a critical role in the formation of ‘fine-grained’ patterns, generating distinct cell fates among groups of initially equivalent neighboring cell and in sharply delineating neighboring regions in developing tissues.

In this project we have achieved the following main goals:

1. We used a combination of micropatterning technology and live imaging track signaling dynamics between pairs of sender and receiver cells in a controlled geometry. We found that signaling between cells correlates with the contact area between the cells. We use a mathematical model to show that such dependence can strongly bias the selection of differentiated cells in lateral inhibition. Finally, we show evidence from the developing chick inner ear that supports the predictions of our model. These results highlight the importance of cell morphology on Notch mediated developmental processes.

2. We used quantitative live imaging assays to measure the diffusion and endocytosis rates of Delta-like 1 (Dll1) in mammalian cells. We found that diffusion coefficients of Dll1 can vary considerably between single cells within the same population with cell-to-cell differences reaching one order of magnitude. We use a simple reaction-diffusion model to show how membrane dynamics and cell morphology affect cell-cell signaling. We find that differences in the diffusion coefficients, as observed experimentally, can dramatically affect signaling between cells, particularly in situations where the contact areas between cells are small. Taken together, our experimental and theoretical results elucidate how membrane dynamics and cellular geometry can affect cell-cell signaling.

These results highlight the successes of the research program supported by the IRG research grant and my successful reintegration at the Tel-Aviv University.