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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - MorphoNotch (Multi-scale analysis of the interplay between cell morphology and cell-cell signaling)

Teaser

Summary

Signaling, genetic regulatory circuits, and tissue morphology are inherently coupled to each other during embryonic development. Although changes in cellular and tissue morphology are commonly treated as a downstream consequence of cell fate decision processes, there are multiple examples where morphological changes occur concurrently with the differentiation processes. This suggests that a feedback between cell morphology and regulatory processes can play an important role in coordinating tissue development. Currently, however, we lack the experimental, theoretical, and conceptual tools to understand this interplay between cell morphology, signaling, and regulatory circuits. In particular, we need to understand (1) how intercellular signaling depends on the cellular morphology and on the properties of the boundary between cells, and (2) how intercellular signaling, genetic circuits, and cell mechanics integrate to generate robust differentiation patterns.

In this project we combine quantitative in-vitro and in-vivo experiments with mathematical modeling to address these questions in the context of Notch signaling and Notch mediated patterning, typically used for coordinating differentiation between neighboring cells during development. Our goals are to elucidate how the geometry and the molecular composition of the boundary between cells affect signaling. At the tissue level, we aim at understanding how the interplay between cell morphology, cell mechanics, and Notch signaling gives rise to robust patterning in the mammalian inner ear. This research will provide the conceptual framework and methodologies required for a systems level understanding of development that interconnects cell morphology, cell mechanics, and regulatory circuits. In the long run, the insights and knowledge obtained in this project are expected to have implications on development of therapeutic approaches based on Notch signaling for diseases such as cancer, as well as the development of regenerative approaches to hearing loss.

Work performed

During the first half of the project we have made significant progress towards achieving our goals. There include:
1. Using a unique micrpatterning device we have shown that Notch signaling is proportional to the contact area between cells (Shaya et al Dev Cell 2017).
2. We have also shown that his dependence of signaling on contact area can bias Notch mediated cell fate decisions such as those occurring in chick inner ear development. (Shaya et al. Dev Cell 2017).
3. Using an inner ear live explant assay developed in the lab, we now show that the gradual organization of Hair Cells (HCs) and Supporting Cells (SCs) in the mammalian inner ear is driven by global shear and local repulsion between HCs in the organ of Corti. This gradual organization occurs through multiple reorganization processes including cell intercalations and delamination processes (Aim 3).

Final results

Significant progress beyond the state of the art include:
1. Development of mathematical model that combine morphology, cell mechanics, cell-cell signaling, and regulatory circuits. These models provide a framework for bridging the gap between the genetic, molecular, and physical forces that drive developmental processes.
2. Novel understanding of the development of the mammalian inner ear. In particular, we now have new insights into the processes that drive the precise patterning of hair cells and supporting cells in the organ of Corti.
3. Development of novel micropatterning devices that allow quantitative analysis of the dependence of Notch signaling on the properties of the contact area between cells and Notch signaling mediated by filopodial contacts.