Regulation of growth and metabolism

Any animal, including human, must grow many times its original size as it develops from an embryo into an adult. This growth is, in part, achieved by an increase in the number of cells, a process known as cell proliferation. The overall aim of this work at the MRC National Institute for Medical Research is to identify the key genes that regulate cell proliferation. Discovering these new genes will further our understanding of what goes wrong in cancer, when cells proliferate inappropriately during adult life. Much of this work utilises the fruit fly (Drosophila) as an efficient gene discovery tool. When the DNA sequences of the Drosophila and human genomes were completed, it became clear that fruit flies possess at least 85% of the genes involved in human diseases. This strong evolutionary conservation, coupled with powerful genetic techniques and a short life cycle, explains why Drosophila research has such an impressive track record in finding the underlying causes of human diseases. Recent research at the National Institute for Medical Research has identified several new genes that are important for switching off cell proliferation in the adult Drosophila brain. Many of these genes work by preventing neural stem cells from producing too many neurons. We have also identified a role for dietary fat in the regulation of overall body growth. We find that a Drosophila internal organ, resembling the human liver, is essential for metabolising dietary lipid into molecules that can then stimulate growth. This work also opens up the possibility of using the power of Drosophila genetics to discover potential new drugs to treat human liver diseases.

The aim of our work is to identify the molecular mechanisms responsible for regulating the growth of the embryo. Growth regulation involves the integration of many different positive and negative signals that can act locally, within one tissue, or globally, to control the overall size of the organism. We wish to identify the molecules and genetic pathways important for stopping cell growth and proliferation towards the end of embryonic development. In the long term, these might provide new therapeutic targets for cancer treatments. In addition, we are investigating how environmental influences such as the composition of the diet can impact on the genes regulating growth and metabolism. This work may provide new insights into the aetiology of human metabolic diseases such as type II diabetes. The driver and gene discovery tool for much of our work is the genetic model organism Drosophila. Currently, we are focusing on two main approaches towards understanding growth regulation in Drosophila. In the first approach, we are studying how the growth of the central nervous system (CNS) is regulated. In particular, we are conducting genetic screens for genes regulating the time at which Drosophila neural stem cells (called neuroblasts) start and stop dividing. Several new neural-stem cell genes identified from these screens are currently being analysed. In the second approach, we are investigating how dietary fat intake influences growth and metabolism during development. As a first step towards this goal, we have identified a Drosophila cell type (the oenocyte) that is specialised for processing lipids and is essential for larval growth. Oenocytes carry out many of the functions of the human liver and can be used to model hepatic steatosis (fatty liver), a pathology associated with type II diabetes.