The search for the holy grail of regenerative medicine— the ability to "grow back" a perfect body part when one is lost to injury or disease—has been under way for years, yet the steps involved in this seemingly magic process are still poorly understood.
Now researchers at the Salk Institute have identified an essential cellular pathway in zebrafish that paves the way for limb regeneration by unlocking gene expression patterns last seen during embryonic development. They found that a process known as histone demethylation switches cells at the amputation site from an inactive to an active state, which turns on the genes required to build a copy of the lost limb.
"This is the first real molecular insight into what is happening during limb regeneration," says first author Scott Stewart, a postdoctoral researcher in the lab of Juan Carlos Izpisúa Belmonte, who led the Salk team. "Until now, how amputation is translated into gene activation has been like magic. Finally we have a handle on a process we can actually follow."
Their findings help explain how epimorphic regeneration—the regrowing of morphologically and functionally perfect copies of amputated limbs—is controlled, an important step toward understanding why certain animals can do it and we cannot.
"Our experiments show that normal development and limb regeneration are controlled by similar mechanisms," explains Izpisúa Belmonte, a professor in the Gene Expression Laboratory. "This finding will help us to ask more specific questions about mammalian limb regeneration: Are the same genes involved when we amputate a mammalian limb? If not, what would happen if we turned them on? And if we can affect these methylation marks in an amputated limb, what effect would that have?"