Systemic regulation of intestinal tissue homeostasis in Drosophila melanogaster. Arshad Ayyaz, Jason Karpac, Heinrich Jasper. Buck Institute for Research on Aging, Novato, CA.

   The breakdown of tissue homeostasis is a hallmark of aging, and barrier epithelia are particularly vulnerable due to their continuous exposure to bacteria and adverse environmental factors. Intestinal stem cells (ISCs) embedded in the intestinal epithelium are capable of regenerating all known cell types of the intestine. It is well established now that under conditions of stress, such as immune challenge, cytokines secreted by damaged enterocytes are sensed by ISCs, triggering a tissue regeneration program. Interestingly, however, intestinal homeostasis is also controlled by systemic factors that influence ISC proliferation. For instance, both neuronally and muscle-derived insulin like peptides (DILPs) activate insulin/IGF (IIS) signaling in ISCs, influencing their proliferation. DILPs are also critical for maintenance of metabolic homeostasis, indicating a key role in coordinating regenerative activity with nutrient availability. It is not clear, however, whether signals from other metabolically important tissues, such as oenocytes or fatbody, also influence regeneration in the intestine, and whether such signals influence tissue homeostasis in aging animals. Furthermore, various domains of the intestine are innervated by nerve fibers, establishing an intestine-brain circuit. It is not known, however, whether regeneration of the intestinal epithelium is influenced by the activity of these neurons. We are exploring these questions by perturbing gene function in selected tissues while monitoring regenerative activity of ISCs. For this, we are developing fly strains that allow labeling stem cell clones using a newly developed gene targeting system, the Q system, thus allowing us to use temperature sensitive Gal4/UAS and Gal80 systems for tissue specific gene manipulations. We will use these flies to perform tissue specific high throughput screens. This work is expected to provide important insight into the systemic regulation of tissue homeostasis and thus into the development of age-related proliferative diseases. Progress on this work will be reported.