For obvious reasons, there is a lot of interest in how regeneration gets started. But have you ever thought about what gets it stopped? We have! Understanding the signals that stop new nerve growth will be important to coaxing our own central nervous system to renew after injury.
Neural Growth Termination
Above: Control (on left) eye regeneration, and regeneration of excess of eyes (on right) following inhibition of PCP.
One of the largest black boxes in regeneration is how an organism decides when patterning is complete. A mechanism to stop regeneration must exist, since planarians do not keeping regenerating new tissue indefinitely. But how this happens is unknown. Our data have revealed that for one tissue, specially the nervous system, the Planar Cell Polarity (PCP) pathway is required for the planarian nervous system to stop regenerating. Without PCP, the entire nervous system continues to grow for months after regeneration normally ends! Strikingly, the excess visual neurons produced result in regenerates that continually make new eyes.
We found that the restriction of neural growth by PCP is conserved in vertebrate regeneration and development, suggesting this is an ancestral role. Together the data reveal PCP inhibition may be a novel target for therapies aimed at initiating nerve regrowth in humans, where damage to the central nervous system is usually permanent. Our current goal is to determine how PCP functions to restrict nerve growth. We are investigating which cells require PCP, how the PCP pathway interacts with stem cells to regulate neural progenitors, and how neural termination is integrated with the mechanisms that control the overall regeneration of shape. The ultimate aim is to identify therapeutic reagents for the initiation of neural regeneration.
Left: The planarian nervous system (in green), consists of a true brain, two ventral nerve cords that run the length of the body, and an intricate network of commissural and peripheral nerves. When PCP is inhibited, the regenerating worm regrows too many commissural neurons (yellow arrows).