Developmental Regulation of Injury-Induced Cell Cycles in the Drosophila Hindgut

As development progresses, many tissues lose their ability to regenerate via cellular proliferation. In some tissues, including the human heart and kidneys, injury activates a non-proliferative cellular response known as hypertrophy- an increase in cell size to restore lost organ mass. Although the connection between development and injury response is often observed, little is known about the developmental signals that terminate and switch injury responses. Moreover, the role of non-proliferative injury responses in restoring function to recovering tissues remains unexplored.

In this dissertation, I identify the Drosophila hindgut pylorus, an intestinal valve, as a new model to study the developmental regulation of injury responses. By using Drosophila genetics and developing a new method for site-specific genetic ablation, I discovered that the Drosophila pylorus switches its injury responses during tissue development. Injury to the larval pylorus results in accelerated mitotic cycles while injury to the adult pylorus leads to endocycles (DNA replication without division) and hypertrophy. My work identifies developmental hormones and transcription factors that act to regulate the injury response switch through control of fizzy-related, an evolutionary-conserved mitotic inhibitor. Last, I found that under chronic growth conditions, endocycles and hypertrophy protect the pyloric epithelial barrier function. Together my work explores both regulation and function of a developmental injury response switch.