Precise patterning of the inner ear

Interplay between mechanics and signaling 

This project is focused on elucidating the development of the mammalian hearing organ, the organ of Corti - arguably the most organized tissue in humans. The organ of Corti has four rows of sensory hair cells (the cells that respond to sound vibrations) interspersed by non-sensory supporting cells forming a highly organized checkerboard-like pattern. We study how the interplay between cell-cell signaling and cell mechanics drive the transition from an initially disordered undifferentiated epithelium to this remarkably organized pattern of hair cells and supporting cells. We combine live explant imaging with mathematical modeling to understand the processes underlying this transition.  
In a recent work, we showed that this gradual organization occurs due to external shear forces that drive the organization of the hair cells into a compact crystal-like state. Thus, the emergence of a precise pattern of hair cells is driven by mechanical forces in process similar to crystallization of atoms in physics.
See more: Cohen et al., Nat Commun (2020).

The right direction

Mechanisms of planar cell polarity

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 use various imaging techniques including live-cell time-lapse confocal imaging, fluorescence recovery after photobleaching (FRAP), and total internal reflection microscopy (TIRF) to characterize the spatial distribution and dynamics of Fat4-Ds1 complexes. These studies provide a quantitative mechanistic framework for understating planar cell polarity (Loza et al., Elife. 2017).

Know thy neighbor

Biophysics of Notch Signaling

Notch signaling is the canonical signaling pathway used for coordination between neighboring cells during development. We study how the molecular and biophysical properties of the Notch signaling pathway control developmental processes mediated by Notch signaling. We use live cell imaging, molecular engineering, and mathematical modeling to obtain quantitative understanding of the Notch pathway. 

projects in this direction include:

  • Elucidating the effect of cell morphology on Notch signaling and Notch mediated patterning (Shaya et al., Dev Cell. 2017)

  • Understanding the factors regulating the Notch transcriptional response (Yi et al., Elife. 2020)

  • Studying the cell surface dynamics of Notch receptor and ligands as well as their interactions

  • Elucidating the interplay between ubiquitylation and receptor-ligand affinity

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