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 combined 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 were to elucidate how the geometry and the molecular composition of the boundary between cells affect signaling. At the tissue level, we aimed 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 provided the conceptual framework and methodologies required for a systems level understanding of development that interconnects cell morphology, cell mechanics, and regulatory circuits.
The grant produced several important scientific papers that highlighted the following conclusions:
(1) Notch signaling depends on the contact area between cells. This dependence can be important for cell fate decisions
(2) The precise pattern of sensory hair cells in the inner is achieved through mechanical forces that drive cellular rearrangements.
(3) Feedback between Notch mediated patterning and mechanically driven morphological changes drive precise hair cell patterning.
(4) Notch signaling is involved in the spatiotemporal coordination of neural stem cells in adult zebrafish brain.
In the long run, the insights and knowledge obtained in this project are expected to have implications on basic understanding of a variety of developmental processes as well as on the potential development of regenerative approaches to hearing loss.
