Coordination of the nutrient response across cell types in a complex organ

点击翻译按钮获取中文摘要

Diet is one of the most important factors influencing animal physiology. Its effects are observed at all biological scales from individual cells, where growth depends on appropriate levels of nutrients, to complex multi-cellular organisms, where diet has a major effect on lifespan and health in old age. Understanding the effects of diet and nutrition on organisms therefore has critical implications for improving human health into old age.Work in cell culture has found that dedicated nutrient sensing pathways in all cells regulate cell growth and proliferation depending on the availability of nutrients. In multi-cellular organisms, by contrast, specific organs are thought to be the sites where nutrient levels are sensed and these regulate the physiology of the whole animal in response to nutrients.Yet it is still poorly understood how individual tissues respond to changes in nutrient levels or systemic signals from these organs. Many organs are made up of many cell types, both differentiated cells that fulfil tissue function, and stem cells that are responsible for providing new cells in response to tissue damage or natural turnover. Given their different roles in the tissue, it is conceivable that different cells do not respond in the same way to starvation.The Drosophila testis is an excellent model to study how complex organs coordinate the response to nutrition. The testis is composed of two broad cell types which are easily identified by their morphology, position within the tissue, and gene expression: germline cells which eventually give rise to sperm, and somatic cyst cells which support germline development. Both cell types are maintained by a separate stem cell population. During starvation, differentiated cells are eliminated through cell death, while stem cells are preserved but in smaller numbers. This makes the testis ideal for studying how nutrient sensing is orchestrated in a complex tissue: do all cells sense nutrients, or is this function restricted to specialised cells in the tissue, or even to a distant tissue? Our initial data show that not all cells in the testis respond to nutrient-sensitive pathways: the Insulin pathway is specifically inhibited in differentiated cyst cells, leading to the death of both cyst cells and germ cells. However, Insulin does not influence the somatic stem cells' behaviour during starvation.Drosophila provides many unparalleled genetic tools which mean that we can manipulate gene expression with cell type and temporal precision and it has proven to be an invaluable model to discover the basic concepts underlying many aspects of animal biology, including the first stem cell niche ever described. In this proposal, we will capitalise on these advantages to ask how the response to nutrition is orchestrated among all these cell types (soma and germline, differentiated cells and stem cells). We will determine how differentiated somatic cells sense changes in nutrient levels, and how they relay this information to germ cells. Next we will ask if nutrients are limiting for stem cells during starvation, or whether stem cells respond to a different signal. Finally, we will determine how distant organs impact on the starvation response of stem cells in the testis.The outcome of our work will be a better understanding of how complex tissues sense and respond to nutrient levels. This knowledge will be beneficial in the long term to help target interventions at specific cell types or pathways that could maintain human health in old age.