What are the signals that allow the correct differentiation of neoblast stem cells during planarian regeneration?

Studying the biology of simple animals has been, and continues to be, invaluable to the understanding of human biology. We kno wthat simple animals (such as flies and worms) use the same basic genes and molecules that humans use for controlling many different biological processes. Their unusual biology makes them ideal subjects for studying certain basic aspects of our own biology. Simple animals have shorter lifecycles, allowing faster progress than in more complex animals. Additionally, simple animals are amenable to experimental approaches that are inappropriate and unethical in complex animals (particularly humans!). In this study, a planarian worm will be used to understand the basic biology of stem cells. Stem cells are cells that retain the ability to become lots of different types of cell such as nerve, muscle or skin cells. Adult planarians are unusual in that they contain a large number of stem cells which are capable of giving rise to every other cell type in the worm. For example experiments at the beginning of the last century showed that if a planarian is cut into small pieces, these prsence of adult stem cells will allow each piece of the worm to regenerate into a whole new, albeit smaller, worm. Growing a new head, arm or leg is something humans obviously can't do. But we do have cells that have some capacity to generate other cell types when they are needed, for example in response to cuts or bruises we are able to heal and replace damaged cells. The intention of this research is to understand how the planarian worm's stem cells are able to divide and give rise to the right cells at the right place in the new worm. If we can understand this process we may be closer to understanding our own capacity to regenerate lost or damaged cells. This type of research is particularly important for understanding diseases in which cells have been lost or damaged and new cells are needed (such as Alzheimers), or for diseases like leukemia where our own stem cells go haywire and produce too quickly or produce the wrong type of cells. The fact that so many bioogical processes are shared between simple animals and that we have developed exoerimental tools to study the in detail an animal that uses stem cells so extensively during its life course is an exciting opportunity to increase our basic understanding of stem cell biology.

Planarians are a classical model for studying regeneration. They employ extensive tissue turnover as part of their normal lifecycle, a process dependent on the presence of an adult stem cell population of potentially totipotent adult stem cells called neoblasts. Molecular genetic technologies to studying these stem cell rich animals, including RNAi and a whole genome sequencing project for the planarian Schmidtea mediterranea, provide a model system to understand animal stem cell biology. We are interested in how cell autonomous and non-cell autonomous signals ensure differentiation of stem cells into the correct cell types at the correct location along the body axis. We will use a combination of classical manipulative experiments that induce defined regenerative scenarios, microarray expression analyses and RNAi based gene knockout to identify genes involved in this process. We will take three synergistic approaches to identify genes required for positional information during regeneration. Firstly, we shall take a candidate gene approach by identifying genes known to be important for positional information and regenerative events in other animals. RNAi will be used to assess possible roles for these genes in specifying positional information during normal homeostasis and regeneration. A second approach will be to assess global levels of gene expression in regenerating planarian tissues at different times and positions along the body axis using microarray expression analyses. RNAi will also be used to investigate the function of these genes during regeneration and homeostasis. Finally, to investigate the signals that confer correct identity during head/brain regeneratiob we will employ a set of classical transplant experiments that subvert normal regenerative events.These experiments combined with the ability to knockdown gene expression by RNAi in both host and donor animals will be used to identify the nature of positional signals.