Improper regulation of adult stem cells and tissue homeostasis is associated with cancers and agedependent decline in tissue function. Therefore, important aims of regenerative medicine are to define mechanisms controlling adult stem cell proliferation and differentiation and to elucidate how these cell fate decisions become defective during aging. Drosophila melanogaster is a developmental model amenable to genetic approaches whose use has given insight into conserved principles of stem cell biology. The Drosophila adult midgut contains large numbers of multipotent adult stem cells (intestinal stem cells, ISCs)] that replenish the gut weekly in healthy animals, but extremely rapidly when confronted with damaging agents. ISCs self-renew and produce a post-mitotic progenitor that terminally differentiates into an enteroendocrine or enterocyte cell). We use this model system to address fundamental mechanisms of stem cell biology. Using a combination of genetic tools, cell biology, and whole-genome DNA sequencing approaches we have achieved the following goals:
1. Determined how terminal differentiation is regulated. 2. Identified novel genes required for self-renewal, many of which are chromatin regulators. 3. Discovered frequent genomic instability of aging adult stem cells.