Appropriate regulation of cell proliferation and differentiation is essential for normal development and maintenance of the nervous system and for neural regeneration following disease or traumatic injury. We are studying neural regeneration in the genetic model system Drosophila melanogaster where we can manipulate neural precursors in the context of an intact brain. We have focused on the adult Drosophila mushroom body, a part of the brain that plays critical roles in learning and memory. Although the neural stem cells undergo apoptosis prior to adulthood, we have shown that the mushroom body can undergo regeneration following injury. Our working hypothesis is that certain types of glial cells adopt neural precursor fates, proliferate, and give rise to both new neurons and new glial cells. The goal of the experiments proposed in this application is to identify the cells that proliferate following injury and understand the process by which they give birth to new neurons and new glial cells. Once we have accomplished the aims described in this proposal, we will be poised to undertake further analyses of Drosophila neural regeneration, including forward genetic screens for regulators of the regenerative process. Our long-term goal is to gain sufficient knowledge of the regulatory gene networks that we can activate neural regenerative programs following disease or injury.
Neurodegenerative diseases represent significant medical problems in the United States. Two of the most common are Alzheimer's Disease and Parkinson's Disease which have lifetime risks of about 1 in 6 and 1 in 60, respectively. Future treatments of neurodegenerative diseases are likely to include the stimulation of adult cells to replace degenerated neurons. We have developed a novel neural regeneration model in the adult brains of the genetic model organism Drosophila melanogaster. Because of the absence of recognizable stem cells and the scarce mitotic activity, it was thought that the adult Drosophila brain has little or no regenerative capacity. However, we have shown that cells in the adult brain can be induced to proliferate following injury, giving rise to both new neurons and new glial cells. This is significant because it indicates that non- canonical stem cells may serve as a functional precursor pool for neural regeneration. The goal of the experiments proposed in this application is to determine the cell types that contribute to the regenerative process and to test the hypothesis that subpopulations of glial cells are able to give rise new neurons. The ability to explore new areas of neural regeneration in the context of an intact brain ultimately wil help us understand and prevent senescence and activate regenerative programs following disease or injury. By demonstrating that in the absence of canonical neural stem cells, it is nonetheless possible to stimulate neural regeneration, we are opening the door for therapeutic approaches based on resident cell populations in any region of the mammalian brain.
| Loewen, Carin; Boekhoff-Falk, Grace; Ganetzky, Barry et al. (2018) A Novel Mutation in Brain Tumor Causes Both Neural Over-Proliferation and Neurodegeneration in Adult Drosophila. G3 (Bethesda) 8:3331-3346 |
