KIF7 and Microtubule Dynamics Function to Regulate Cellular Proliferation and Cell Cycle Progression

Abstract

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Biomedical Genetics, 2015.Respiratory diseases such as lung cancer, COPD, and asthma are the second leading cause of death in the United States. These diseases are heterogeneous and arise from genetic factors, environmental hazards, or congenital abnormalities that persist throughout life. An increased understanding of the genes and cellular mechanisms regulating respiratory system homeostasis and regeneration should provide information for the development of future therapeutics. We performed a forward genetic screen in mice aimed at identifying novel genes and mutation required for respiratory system function in the laboratory mouse, Mus Musculus. We indentified a mouse mutant line with tissues patterning, and tissue hyperplasia phenotypes. We determined that the causative mutation occurred within the cilia and microtubule associated gene Kinesin family member 7, Kif7. By characterizing the phenotypes of Kif7 mutant mice and Kif7 depleted cells, we identified several novel functions for this molecule. We show that the gene Kif7 regulates cell proliferation, cellular density, and intracellular signaling within the epithelial and mesenchymal cells of the respiratory airway. We expand on the known role for KIF7 by showing that this protein functions to maintain cytoskeletal microtubule organization and controls fibroblast cellular density and to regulate cell cycle progression and cell signaling in non-ciliated secretory cells. Furthermore, we show that microtubules function to regulate the abundance and activity of several factors known to be required for proper cell cycle timing. We propose that KIF7 and microtubule dynamics hone cellular signaling necessary for control of the balance between cell proliferation and cell cycle exit, and we provide evidence that Kif7 has a critical role in the maintenance of the respiratory system in postnatal life