Physiological and Regenerative Homeostasis in Drosophila

The central objective of developmental biology is to understand how organisms grow to adulthood. In the past 30 years, studies using genetically tractable model systems have led to a detailed understanding of the genetic mechanisms involved in the control of developmental events, as illustrated by our intimate knowledge of patterning and morphogenesis. The next big questions are how complex phenotypes arise in the context of the whole organism and how the programs regulating their development and function are influenced by genetic background and environment. For example, little is understood about how the simultaneous growth and differentiation of different tissues are coordinated and how the development of different cell types and tissues is integrated within an organ. Further, many of the mechanisms by which growth factor-triggered signaling events intersect with cell metabolism, which is regulated by nutrients and hormones, remain to be identified.

We are using Drosophila as a model system to characterize the responses of specific cells to extracellular signals. Previous work from our laboratory has focused on the characterization of the signaling pathways that orchestrate embryonic patterning and morphogenesis. More recently however, as we now have a rather good knowledge of these processes, we have become more interested in studying: 1. the mechanisms involved in the control of cell and tissue growth, and especially the roles of the Insulin pathway in these processes; and 2. how signaling mechanisms are used in the context of homeostasis. ‘Homeostasis’, from the Greek words for ‘same’ and ‘steady’, refers to ways in which the body acts to maintain a stable internal environment despite perturbations. We are interested in two kinds of homeostatic regulation: 1. “Physiological Homeostasis” that encompasses the mechanisms by which differentiated tissues, such as muscles, grow and maintain their mass during the aging process; and 2. “Tissue/Regenerative Homeostasis” that addresses the maintenance of tissue integrity by stem cell systems, as is the case of the gut that exhibits slow regeneration under normal conditions but accelerated regeneration when injured. We are studying these fundamental problems in Drosophila because the fly is one of the prime model systems for studying the basis of human diseases and, arguably, has an unmatched arsenal of tools for both in vivo and in vitro functional genomic studies. Ongoing work in our laboratory can be subdivided into four categories:

First, to facilitate Functional Genomic approaches in Drosophila, we develop, improve, and generate reagent resources to make the process of gene discovery and identify genes’ function both in vivo and in vitro/tissue culture faster, easier, more reliable, and genome-wide. Importantly, to maintain and build on the Drosophila community’s tradition of sharing, that was pivotal to establish Drosophila as one of the premier model systems, we make the methods and reagents that we develop immediately available to the community.

Second, we apply these tools to tissue culture cells to elucidate the organization of the core Cell Circuitry networks involved in signaling. Our approach, based on genome-wide RNAi screening, proteomic and computational analyses, is to identify the parts responsible for the reception and integration of the signals, organize them into pathways and networks, and then validate the findings in more complex in vivo biological systems; i.e., muscles and gut stem cells.

Third, as a model for Physiological Homeostasis, we study Drosophila muscles to identify the molecular mechanisms involved in their growth, maintenance, and aging. Specifically, we are interested in: 1. the mechanisms underlying sarcomere formation; 2. the roles of the Insulin pathway in muscle growth; 3. the roles of microRNAs in Insulin and muscle homeostasis; 4. the roles of autophagy in muscle mass maintenance; 5. the molecular mechanisms of muscle aging; and 6. the roles of mitochondria in muscle growth and homeostasis. In particular, we are interested in validating the information generated from the cell circuitry studies described above using assays related to these biological questions.

Fourth, as a model for Tissue/Regenerative Homeostasis, we study the mechanisms that control the proliferation of Drosophila adult gut stem cells in both normal and injured conditions. Specifically, we are interested in: 1. establishing “cancer” stem cell models by activating a number of oncogenes or downregulating the activity of a number of tumor suppressors in the ISCs; 2. performing genetic and chemical whole-animal screens to identify genes and small molecules that are required for growth and survival of “cancer” stem cells, but not their wild type counterparts; and 3. studying the effect of dietary restriction on the homeostasis of the gut and the how diet and autophagy influences cell proliferation in the ISC “cancer” models.