Collaborative Research: RUI: Comparative analysis of endocytic trafficking during cell division

This research project explores the interplay between cell division and the signals that cells exchange to coordinate their behavior. This is a critical area of investigation because signal-dependent coordination of cell behavior is essential for the growth of all life forms. Signaling also plays a crucial role in dividing stem cells, ensuring that the proper number of stem cells are available to participate in tissue renewal and repair.

Additionally, errors in signaling are the primary cause of cancer. Because cancer also entails unregulated cell division, it is particularly important to understand how division may exacerbate signaling errors. To explore this fundamentally important question, this collaborative research project encompasses three institutions, Princeton University, Swarthmore College and Colby College.

The combined expertise will enable comprehensive investigations of signaling in dividing cells using an array of organisms, along with cutting edge genetic manipulation and imaging technologies. Additionally, this collaboration will pursue an ambitious outreach program which will include – 1) providing enriching research experiences for a diverse group of undergraduates, 2) development of a class focused on cancer biology for elementary school students in an underserved school district as part of the established Science for Kids summer program at Swarthmore College, 3) integration between Summer Scholars Programs at Colby, Princeton and Swarthmore which focus on preparing URM and other diverse students for a successful college transition and 4) teacher-training opportunities at the Colby Center for Teaching and Learning for Princeton post-docs who will be teaching courses in the Colby January Term program.

Cellular trafficking of receptors and associated membrane proteins can profoundly impact cell signaling. Due to the long-held assumption that membrane trafficking is shut down during mitosis, current research has not addressed fundamental questions regarding the nature and regulation of trafficking in dividing cells. In particular, the contributions of mitotic kinases to endocytic trafficking remain poorly characterized.

Additionally, the roles of specific endocytic pathways have not been delineated. This project aims to fill these critical gaps through a collaborative effort incorporating two experimental systems in which prior research has demonstrated an essential role for mitotic trafficking: polarization of mammalian epidermal cells and induction of heart progenitor cells in the basal chordate, Ciona intestinalis.

It will investigate two hypotheses; 1) Cyclin dependent kinase 1 (CDK1) suppresses lysosomal degradation in a cargo-specific manner. 2) CDK1 and Aurora Kinase (AurK) suppress recycling broadly during mitosis. These hypotheses will be examined with well-established methods that disrupt specific mitotic kinases and endocytic pathways and employ high-resolution live-imaging assays to visualize the impact on receptor trafficking in both model systems.

By conducting these studies on a range of cargo proteins in two highly divergent cell types, these findings will provide insights into the impact of mitotic trafficking on – 1) fate decisions in developing embryos 2) re-establishment of polarity in dividing epithelial sheets and 3) signal dependent behaviors of stem cells or differentiated lineages.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.