CAREER: Cell Specific Analysis of Conserved Spindle Orientation Factors

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Cells are building blocks for tissues and organisms, and like building blocks, they need to be correctly placed in order to make the right structure. The direction in which a cell divides with respect to the tissue around it determines the position of the two daughter cells. This direction can therefore contribute to tissue shape; for example, oriented cell divisions are implicated in building the tubes that help comprise the lung and kidneys. Placement can also contribute to cell type diversity; oriented cell divisions help to explain how the brain is populated with a range of different cell types. This project takes advantage of recent technical advances in both microscopy and CRISPR-mediated genome editing to examine division orientation across multiple cell and tissue types in the model organism Drosophila melanogaster. This work will resolve the molecular mechanisms that orient cell divisions with respect to the tissue. The Broader Impact include the intrinsic nature of the research as all multi-cellular organisms utilize asymmetric divisions to sort cells in tissues. Additional activities include promoting diversity in science, the training of high school, undergraduate and graduate students, along with post-doctoral researchers.Cell division is controlled not only in time, but also in space. Regulated division orientation can drive asymmetry, as is often the case with stem or progenitor cells that produce daughters with different cell fates, and is also implicated in determining tissue shape and size. Previous work shows that division orientation is determined at metaphase, and is controlled by an evolutionarily conserved set of proteins. These proteins, which include the microtubule motor dynein, combine to produce a pulling force that acts on the mitotic spindle, drawing it into a particular alignment. In order to function correctly, the pulling force must be restricted to a particular region of the cell periphery. However, the precise location must vary according to the cell type. The mechanisms that control localization of the pulling force are unclear, and appear to be diverse. The investigator proposes firstly to study how the pulling force is localized across cell types. He proposes secondly to study a critical spindle orientation factor called Mud (in flies), NuMA (in vertebrates) and LIN-5 (in nematodes), and to determine the function of endogenous variants that are not predicted to promote localized pulling.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.