CAREER: Spatiotemporal organization of cytokinetic events

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Cells employ multiple processes to grow and proliferate. Most cellular processes are highly complex, involving multiple steps that have to be precisely regulated both in time and within the correct region. Inability to organize these steps often leads to cell death. It is not clear how cells sense and signal these different steps during complex processes to ensure proper function. This project will investigate the complex multi-step process of cytokinesis, the final step in cell division. During cytokinesis, a series of steps ensures that a mother cell splits into two intact daughter cells. Using Schizosaccharomyces pombe, or fission yeast, as a model system, signaling patterns that organize different cytokinetic steps will be researched. Preliminary data show that different signaling proteins crosstalk to properly organize these steps. In this project the molecular mechanism of such a crosstalk and how it organizes cytokinetic steps will be investigated. The project will lead to an understanding of the principles that allow cells to sense and signal complex processes. These principles are applicable to higher organisms given that most of the signaling pathways investigated are highly conserved. This project will also involve the design of lab-based cell biology courses for high school and undergraduate students. The principal investigator, a high school science teacher, and a graduate student will be involved in developing the lab-based course. Graduate, undergraduate, and high school students will also be trained in conducting research. Students will be trained in experimental design, analysis and interpretation and their critical thinking capabilities will be honed. Under-represented undergraduate and high school students will participate in this project through the Educational Advancement Program and Upward Bound program respectively. All the trainees will be trained to present their research at national or international meetings.Cytokinesis, the final step in division, is a universal process in all eukaryotes in which a cell physically separates into two daughters after nuclear division. Successful completion of cytokinesis requires multiple steps that are sequentially coordinated. Disruption of the proper order of these steps can impair the genetic integrity of the progeny, lead to cell separation failure, or cause cell lysis. The goal of this project is to mechanistically define how different cytokinetic steps are spatiotemporally organized. Previous research showed the small GTPase Cdc42 to be required for initiation of septum formation during cytokinesis in fission yeast. Preliminary data show that Cdc42, crosstalk with other RHO GTPases, Rho1 and Rho4, to organize distinct cytokinetic events. Cdc42-Rho crosstalk has also been reported in wound healing, cell migration, and cell polarization. However, it is not known how crosstalk between different pathways coordinate multiple steps during cellular processes. This project will use cytokinesis as a paradigm to mechanistically define crosstalk between GTPases and explain how this enables coordination of complex multi-step processes. The project will involve interdisciplinary approaches with live cell 4D microscopy, molecular nano-traps, electron microscopy, and mathematical modeling. The project will also develop inquiry-driven cell biology lab courses to train future scientists in their quest to investigate the rules of life.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.