Model supports asymmetric regulation across the intercellular junction for collective cell polarization
Authors: Levandosky Katherine , Copos Calina 
Published: June 2024

Symmetry breaking, which is ubiquitous in biological cells, functionally enables directed cell movement and organized embryogenesis. Prior to movement, cells break symmetry to form a well-defined cell front and rear in a process called polarization. In developing and regenerating tissues, collective cell movement requires the coordination of the polarity of the migration machineries of neighboring cells. Though several works shed light on the molecular basis of polarity, fewer studies have focused on the regulation across the cell-cell junction required for collective polarization, thus limiting our ability to connect subcellular interactions to tissue-level dynamics. Here, we investigate how polarity signals are communicated from one cell to its neighbor to ensure coordinated front-to-rear symmetry breaking with the same orientation across the group. In a theoretical setting, we exhaustively search a variety of intercellular interactions and identify the conditions required for the Rho GTPase signaling module and/or cytoskeletal dynamics to achieve either co-alignment arrangement or supracellular arrangement of the polarity axes in a group of 2 and 4 cells. Our work shows that only asymmetric regulations are favorable – such interactions involve either up-regulation of the kinetic rate of complementary polarity components or opposite regulation of the kinetic rates of the same polarity components across the cell-cell junction. Surprisingly, our results hold if we further assume the presence of an external stimulus, intrinsic cellular variability, or larger group size. The results underline the potential of using quantitative models to probe the molecular interactions required for macroscopic biological phenomena. Lastly, we posit that asymmetric regulation is achieved through junction proteins and predict that in the absence of cytoplasmic tails of such linker proteins, the likeliness of doublet co-polarity is greatly diminished.

Author summary

Cells of the developing embryo undergo a highly complex chain of events that define their correct shape and positioning. Among these events, a crucial role belongs to coordinated cell movement of cells of different lineages over short and long distances to give rise to mature organs and organ systems. During collective movement, individual cells typically engage their autonomous polarity machinery, while being connected to their neighbors through adhesive cell-cell interactions. Despite advances in revealing the cell-cell interactions required for collective cell migration, a comprehensive picture of the molecular basis of intercellular communication for collective guidance is missing. To address this question, we devise a generalized mechanochemical model for cell polarity in a doublet and investigate how polarity signals are transmitted from one cell to another across seemingly symmetrical junctions. We have chosen to screen through all possible intercellular conditions of the Rho GTPase signaling circuit and/or cytoskeletal dynamics. Our systematic approach provides information on over 300 distinct conditions and reveals the intercellular regulation provided by junction proteins. In addition to predicting that only asymmetric interactions favor co-polarization, ensuring movement of the group in the same direction, our analysis also highlights the need for additional regulatory mechanisms for larger cell groups.