Spatial re-patterning of stem cell lineages during brain regeneration in freshwater planarians

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Most organisms have at least some capacity to regenerate following injury, although it is clear that many species have lost this during evolution. For example a newt can regenerate from limb amputations and spinal cord transections, while mammals have largely lost the ability to regenerate significant body parts and are extremely poor regenerators of nervous tissue. It is currently unknown why humans cannot recover from severing of the spinal cord, but part of the block is the lack of ability to replace the damaged cells via stem/progenitor cell proliferation and subsequent differentiation. To understand regeneration, it is critical to use a model system that has high regeneration capacity, a central nervous system, stem/progenitor cells, and the ability to test gene function. The freshwater planarian (flatworm, Lophotrochozoan) is an ideal model system to study brain regeneration and stem cell biology. Planarians have a large population of adult stem cells which allow them to regenerate any missing body part that is lost to injury, and can even regenerate an entire head, brain, and eyes in the span of 7 days. In this proposal, we hypothesize that head regeneration can be broken down into 2 processes. First is the spatial choice to make a head vs. a tail. We propose that this will use well-known spatial patterning genes (HOX genes). Second, stem cell proliferation and differentiation must make the cells of the new brain. We will test the function of neural patterning genes to see whether genetic mechanisms during planarian brain regeneration are similar to the genetic mechanisms during brain development in other systems. This work will provide the first data on which genetic pathways are used by planarian stem cells to regenerate a functional brain in both time and space as well as provide molecular insight into brain evolution. Our long-term goal is to use the unique advantages planarians offer to learn how adult stem cells coordinate spatial patterning and lineage differentiation to correctly replace missing tissues.