14 NSFBIO: Asymmetric division and the temporal dynamics of cell motility

This project aims to define the fundamental mechanisms controlling cell migration during organ development. In growing tissues, cells usually replicate by symmetric division (or mitosis) to produce two identical daughter cells. But in some instances cell divisions are asymmetric and give rise to intrinsically distinct daughters. Asymmetric divisions play important roles in differential cell fate decisions, but have never previously been implicated in generating daughters with distinct motilities. This project will explore the molecular and cellular basis of post-mitotic asymmetry in cell motility and define the functional role of asymmetric divisions in the control of cell migration during tissue growth. In particular this work will evaluate how asymmetries is daughter cell signaling, shape and stiffness can profoundly affect cell motility following division. Not only will this research generate freely available novel computational methods and analysis tools suitable for a wide array of applications, the findings of this work will have wide-reaching implications for understanding the control of cell migration across a plethora of cellular systems and organisms. The project will additionally expose undergraduate and high school students (with emphasis on recruiting underrepresented groups) to integrated cross-disciplinary computational / experimental scientific approaches and provide hands-on experience of international collaborative research techniques upon the creation of several new, targeted, interactive Global Interface Science (GIS) workshops. Moreover, guidance on implementing similar GIS workshops anywhere worldwide will be widely disseminated via online media.

Asymmetric cell division (ACD) specifies differential daughter cell fates in many systems, but has never before been implicated in determining the temporal dynamics of cell motility. This project will define how ACD acts as a novel symmetry-breaking mechanism to ensure daughter cells acquire distinct motilities during tissue growth. An integrated in silico and in vivo approach will be taken, innovating a novel multiscale hybrid, spatiotemporal agent-based model (ABM) that will inform single-cell live imaging experiments of endothelial cells in zebrafish embryos. These studies will probe ACD in motile cells, validate model predictions and altogether elucidate a previously unexplored role for mitosis in the control of migration. In particular, the interplay of ACD with cell signaling, geometry and mechanical motility cues across different scales, from the molecular to the cellular will be investigated through the following tasks: A) develop new modeling methodologies to investigate the role of localized intracellular dynamics in the establishment of asymmetric post-mitotic motility and functionally validate model predictions at sub-cellular resolution in vivo; B) Predict the effects of ACD-driven differences in cell architecture on motility dynamics in silico alongside quantification of dynamic alterations in cell architecture occurring during division in vivo; C) quantify pre- and post-mitotic fluctuations in cell tension at single-cell resolution in vivo and define the interplay of cell tension with the induction of ACD and differential motility in silico and in vivo. The products of this research will include novel computational ABM models and image analysis software, which will uniquely enable studies of key aspects of cell migration and will be made freely available to the wider scientific community.

This project will produce societal impacts by:

1) providing new computational methods and image analysis software, made freely available via the PI's websites for the benefit of the
wider scientific community

2) international workshops will be organized to disseminate research outcomes and provide a platform for promoting integrated in silico/in vivo approaches

3) a broad range of populations, ranging from high school and undergraduate students to faculty, will experience unique training that will promote and cultivate cross-disciplinary, international collaborative research. Specific efforts will be made to attract underrepresented groups in science and engineering (STEM) subjects

4) The materials for implementing educational workshops will be widely disseminated via online media for other interested institutes to implement all over the world