Cell Type-Specific Response to Spindle Misorientation and Effects on Tissue Growth

Amalia Parra, Doctoral Student, Biology

Description

Coordination of cell polarity and spindle orientation with cell growth and proliferation ensures mitotic fidelity and thus proper animal development. Mitotic errors have been associated with aberrant tissue growth in both epithelial cells and stem cells. Mutations in cell cycle-promoting genes in neural stem cells cause a mild increase in the Drosophila central nervous system (CNS). Conversely, identical mutations in Drosophila imaginal wing discs (IWD), terminally differentiated cells, lead to massive tissue overgrowth. The mechanisms underlying the differential responses of these cells to errors in cell division, however, are unknown. Here we seek to build a stem cell model and a differentiated cell model to elucidate the varied tissue- specific responses. We found that mutated growth-promoting genes cause substantial overgrowth in epithelial cells, while no significant change in the CNS was observed when expressed in neural stem cells. Additionally, spindle misorientation results in apoptosis-mediated inhibition of growth of IWDs in response to mutated growth-promoting genes. Our results further highlight the differential response of epithelial cells and stem cells to mutated growth-promoting genes. Taken together, these results point to an overgrowth-inhibitory mechanism in epithelial cells stemming from errors in spindle orientation caused by these mutations. Further analysis will provide a better understanding of the cell signaling pathways that govern tissue level responses to defective cell division, both of which are important in understanding the underlying molecular bases for numerous human diseases.

 
Nov 8th, 8:30 AM Nov 8th, 12:30 PM

Cell Type-Specific Response to Spindle Misorientation and Effects on Tissue Growth

Coordination of cell polarity and spindle orientation with cell growth and proliferation ensures mitotic fidelity and thus proper animal development. Mitotic errors have been associated with aberrant tissue growth in both epithelial cells and stem cells. Mutations in cell cycle-promoting genes in neural stem cells cause a mild increase in the Drosophila central nervous system (CNS). Conversely, identical mutations in Drosophila imaginal wing discs (IWD), terminally differentiated cells, lead to massive tissue overgrowth. The mechanisms underlying the differential responses of these cells to errors in cell division, however, are unknown. Here we seek to build a stem cell model and a differentiated cell model to elucidate the varied tissue- specific responses. We found that mutated growth-promoting genes cause substantial overgrowth in epithelial cells, while no significant change in the CNS was observed when expressed in neural stem cells. Additionally, spindle misorientation results in apoptosis-mediated inhibition of growth of IWDs in response to mutated growth-promoting genes. Our results further highlight the differential response of epithelial cells and stem cells to mutated growth-promoting genes. Taken together, these results point to an overgrowth-inhibitory mechanism in epithelial cells stemming from errors in spindle orientation caused by these mutations. Further analysis will provide a better understanding of the cell signaling pathways that govern tissue level responses to defective cell division, both of which are important in understanding the underlying molecular bases for numerous human diseases.