Research

During development, cells undergo dramatic changes in their morphology. These morphological changes can have a strong influence on the ability of cells to communicate, and ultimately on the differentiation patterns generated in the developing organism. Our research focuses on the effect of cell morphology on Notch signaling, which is the canonical juxtacrine signaling pathway in Metazoans, and is often involved in coordinated patterning processes such as lateral inhibition. In order to study the role of contact geometry on Notch signaling, we use both quantitative experiments and mathematical models. We combine micropatterning technology with state of the art microscopy (live confocal imaging, TIRF-FRAP, super resolution imaging) to study the dynamics of Notch receptors and ligands on the cell surface and how these dynamics affect signaling. We also develop mathematical models to understand the biophysical processes affecting Notch signaling and the effect of these processes in various developmental systems.

Planar cell polarity (PCP) is the process by which sheets of cells, typically in the form of epithelial cell layers, acquire an orientation within the plain of the sheet. Recent studies highlighted the role of the atypical cadherins Fat and Dachsous (Ds) in this process. We use a synthetic biology platform, based on a mammalian cell culture system expressing different variants of Fat4 and Ds1 to quantitatively study the formation of Fat4-Ds1 complexes at the interface between cells. We combine this platform with a recently developed micropatterning technology which allows studying interaction between cells in a controlled two-cell and three-cell geometry. We use various imaging techniques including live-cell time-lapse confocal imaging, fluorescence recovery after photobleaching (FRAP), total internal reflection microscopy (TIRF), and direct stochastic optical reconstruction microscopy (dSTORM) to characterize the spatial distribution and dynamics of Fat4-Ds1 complexes. These studies provide a quantitative mechanistic framework for understating planar cell polarity.

Development is not only limited to the realm of biochemistry, genetics and signaling; it also occurs in the physical realm where shape, motion and forces, do matter. How do cell and tissue mechanics affect, and are affected by, regulatory processes within cells? How can accurate differentiation patterns emerge from the complex interplay between these two key aspects of development? Despite the tremendous progress in the understanding of biological systems, we still lack the basic conceptual, theoretical, and experimental tools to address these questions.

We address these questions using the mammalian inner ear as a model system for studying robust morphogenesis. The auditory organ within the inner ear, the cochlea, contains a remarkable checkerboard-like structure with four aligned rows of sensory hair cells extending along its spiral windings. Within several days of development, the sensory epithelium undergoes a transition from an undifferentiated disordered tissue to the precisely patterned terminally differentiated state. This transition involves spatially coordinated differentiation of cells as well as dramatic changes in the morphology of the whole tissue and of the individual cells, and hence can serve as the perfect testbed for studying the interplay between differentiation circuits and tissue mechanics.

We combine a novel modeling approach with a quantitative experimental setup to elucidate the interplay between tissue mechanics and regulatory processes in the cochlea. On the modeling side, we develop hybrid modeling approaches combining models of regulatory networks and mechanical models describing how the position and shape of each cell evolves to a state of minimal energy. On the experimental side, we employ a cochlear explant setup, which allows live 3D imaging of the complete development of the cochlea ex-vivo. The combination of