Stem cells can proliferate, amplifying the number of stem cells or producing more differentiated progeny, or end proliferation by entering quiescence, dying, or otherwise exiting the stem cell pool. How these diverse behaviors are regulated at the level of individual stem cells is poorly understood. In the developing nervous system, the precise control of neural stem cell behavior is important for proper neurogenesis and homeostasis. Neural stem cells end proliferation through a variety of mechanisms, but it is not clear how these terminal cell fate choices are regulated. The Drosophila nervous system provides an ideal model to study the regulation and execution of these terminal events in stem cells due to the extensive mapping of stem cell identity, description of genes required for stem cell behavior, and the powerful tools available to manipulate gene expression. We have identified a previously undescribed non-apoptotic loss of neural stem cells in the embryonic ventral nerve cord. We propose to test the hypothesis that the terminal fate of embryonic neural stem cells is set early in development by spatial and temporal factors. We will identify markers for cells that undergo non-apoptotic loss, and describe the mechanisms of this loss. Building on our previous studies on the regulation of the apoptotic death of neural stem cells, we will identify regulators of non-apoptotic loss, and examine the relationship between the regulators of these stem cell behaviors. At the conclusion of this work, we will have developed an understanding of non-apoptotic stem cell loss, and set the groundwork for examining the regulatory relationships between varied forms of stem cell loss and survival. Learning how neural stem cells are lost in the context of normal development will be critical in understanding how to preserve stem cells to treat diseases such as neurodegeneration.
Stem cells are defined by their ability to proliferate and produce more differentiated progeny. For normal nervous system development, neural stem cells must also terminate proliferation at the proper time, often through becoming quiescent or undergoing apoptotic or non-apoptotic loss. We will investigate the mechanism and regulation of non-apoptotic neural stem cell loss using the powerful tools available in the Drosophila model system.
