NSF/BIO-DFG: Tuning Microtubule-Actin crosstalk to control Mitotic Fidelity

University Of Washington, Seattle WA

Investigators

Abstract

Microtubules are relatively long cellular polymers that continuously grow and shrink in a dynamic yet controlled manner. They are also responsible for segregating chromosomes with perfect fidelity during cell division. Previously it has been found that measurable disturbances in dynamic microtubule growth that do not superficially appear abnormal will promote intermittent errors in chromosome segregation through an unknown mechanism. As everyone who owns a car knows, intermittent defects are the most challenging to diagnose. However, strong preliminary evidence indicates that these small changes in microtubule assembly may temporarily promote the delivery of molecules to the cell outer cortex that interfere with the mitotic spindle’s ability to position itself in space. This, in turn, increases the rate that cells make errors during cell division. Describing this biological phenomenon will prove important to understand the regulation of growth and development in both plants and animals. The Broader Impacts of the work includes its intrinsic merit as all dividing eukaryotic cells employ microtubes for division. Moreover, errors in the process can result in a variety of human maladies. Additional activities include the training of undergraduate and graduate students in research methods and incorporation of the research into an existing course. This project will employ high resolution live imaging, atomic force microscopy and actin reporters to catch mitotic spindles “in the act” of temporarily losing spatial positioning during controlled experimental alteration of microtubule growth rates. A custom method of quantifying attachment errors using super-resolution expansion microscopy will be employed to directly correlate the number of segregation errors commensurate with spindle orientation. The project includes developmental systems to determine the extent to which these mechanisms, initially described in cell culture, are utilized during normal development and in the establishment of tissue architecture. This collaborative US/German project is supported by the US National Science Foundation (NSF) and the Deutsche Forschungsgemeinschaft (DFG) where NSF funds the US investigator and DFG funds the German partner. 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.