Investigating Cell Cycle Re-entry in the Drosophila brain: From the Pupa to the Adult

Abstract

G0 associated with terminal differentiation represents the most common cellular state in adult multicellular organisms, yet it is poorly understood. In past years, various tissues of the fruit fly Drosophila melanogaster have served as a great model system to understand how cells establish and maintain their non-dividing state. While the Drosophila brain has been extensively studied in the context of neurodevelopment, relatively little is known about how the flexibility of cell cycle exit in terminally differentiated neurons and glia. In Chapter 2 of my dissertation, I show that postmitotic neurons and glia in the developing Drosophila pupa brain can be forced to re-enter the cell cycle and undergo mitosis after they have exited the cell cycle. Neurons can re-enter the cell cycle up to 24 hours after they have exited the cell cycle whereas glia exhibit greater flexibility and can undergo cell division up to over 48h after they exit the cell cycle. Forcing re-entry in neurons results in cell death, while glial cell division can result in tumor-like growths. Neurons and glia are some of the longest lived cells in metazoans. How these cells deal with ageing-related damage is poorly understood. My work summarised in Chapter 3 shows that polyploid cells accumulate in the adult fly brain and that polyploidy protects against DNA damage-induced cell death. Multiple types of neurons and glia that are diploid at eclosion, become polyploid in the adult Drosophila brain. The optic lobes exhibit the highest levels of polyploidy, associated with an elevated DNA damage response in this brain region. Inducing oxidative stress or exogenous DNA damage leads to an earlier onset of polyploidy, and polyploid cells in the adult brain are more resistant to DNA damage-induced cell death than diploid cells. Our results suggest polyploidy may serve a protective role for neurons and glia in adult Drosophila melanogaster brains.