Dieterle, P. | Search bioRxiv

bioRxiv2024

Measuring and modeling the dynamics of mitotic error correction

Error correction is central to many biological systems and is critical for protein function and cell health. During mitosis, error correction is required for the faithful inheritance of genetic material. When functioning properly, the mitotic spindle segregates an equal number of chromosomes to daughter cells with high fidelity. Over the course of spindle assembly, many initially erroneous attachments between kinetochores and microtubules are fixed through the process of error correction. Despite the importance of chromosome segregation errors in cancer and other diseases, there is a lack of methods to characterize the dynamics of error correction and how it can go wrong. Here, we present an experimental method and analysis framework to quantify chromosome segregation error correction in human tissue culture cells with live cell confocal imaging, timed premature anaphase, and automated counting of kinetochores after cell division. We find that errors decrease exponentially over time during spindle assembly. A coarse-grained model, in which errors are corrected in a chromosome autonomous manner at a constant rate, can quantitatively explain both the measured error correction dynamics and the distribution of anaphase onset times. We further validated our model using perturbations that destabilized microtubules and changed the initial configuration of chromosomal attachments. Taken together, this work provides a quantitative framework for understanding the dynamics of mitotic error correction.

cell biology↗

bioRxiv2019

Dynamics of diffusive cell signaling relays

Cells can communicate with each other by emitting diffusible signaling molecules into the surrounding environment. However, simple diffusion is slow. Even small molecules take hours to diffuse millimeters away from their source, making it difficult for thousands of cells to coordinate their activity over millimeters, as happens routinely during development and immune response. Moreover, simple diffusion creates shallow, Gaussian-tailed concentration profiles. Attempting to move up or down such shallow gradients - to chemotax - is a difficult task for cells, as they see only small spatial and temporal concentration changes. Here, we demonstrate that cells utilizing diffusive relays, in which the presence of one type of diffusible signaling molecule triggers participation in the emission of the same type of molecule, can propagate fast-traveling diffusive waves that give rise to steep chemical gradients. Our methods are general and capture the effects of dimensionality, cell density, signaling molecule degradation, pulsed emission, and cellular chemotaxis on the diffusive wave dynamics. We show that system dimensionality - the size and shape of the extracellular medium and the distribution of the cells within it - can have a particularly dramatic effect on wave initiation and asymptotic propagation, and that these dynamics are insensitive to the details of cellular activation. As an example, we show that neutrophil swarming experiments exhibit dynamical signatures consistent with the proposed signaling motif. Interpreted in the context of these experiments, our results provide insight into the utility of signaling relays in immune response.

biophysics↗