How Do Some Animals Regenerate? It's All About Gene Regulation

Humans appear to have lost regenerative ability somewhere down the evolutionary line, but new research is revealing how gifted animals repair themselves - and how regeneration might be restored in humans

Creatures like the salamander and humble zebrafish perform stunning feats of regeneration and it's likely humans share a common ancestor that was able to do the same. Somewhere along the line however this ability was lost, perhaps because it had minimal effect on the survival of the species. We know humans have many counterparts to genes tied to regeneration other animals, but they're simply not doing the same job. New work on zebrafish is now revealing that the secret may lie not in the genes themselves, but in their regulatory sequences. 

The secrets lies with TREES

Many genes have been discovered that allow regeneration in other animals, like neuregulin 1 which allows heart muscle cells to proliferate. In a fresh effort to understand what's going on researchers decided to look for regulatory sequences that could be switching on the activity of these particular genes. They discovered that beside these genes already connected to repair are regulatory elements they call tissue regeneration enhancer elements (TREES). These appear to turn on specific genes when the animal is injured, allowing it to regrow lost tissue. 

Credit: ajcann.wordpress.com

"We want to know how regeneration happens, with the ultimate goal of helping humans realize their full regenerative potential. Our study points to a way that we could potentially awaken the genes responsible for regeneration that we all carry within us"

 

 

The lead author of the study Junsu Kang examined zebrafish with injured hearts or amputated fins and discovered that one gene called leptin b was activated in both. After further analysis of their DNA, an enhancer element was discovered that was responsible for activating the damage response. Enhancer elements control gene expression - switching them on in response to particular signals like tissue damage in this case. By dissecting this enhancer sequence, it was found that it contained two separate sequences that each responded to either heart or fin damage. Fusing these 2 enhancer sequences next to 2 known 'regeneration genes' actually improved the regeneration response in zebrafish. 

Testing TREES on mammals

That's all well and good for zebrafish, but could it helps mammals to recover lost regenerative abilities? The team coupled the TREE sequence with a gene called lacZ which turns blue when it's activated. They then delivered this sequence into mice and observed what happened when mice paws or hearts were injured. Amazingly, the injury appeared to turn on gene expression in the mice as well. 

Regeneration is actually fairly widespread in nature

"We are just at the beginning of this work, but now we have an encouraging proof of concept that these elements possess all the sequences necessary to work with mammalian machinery after an injury" 

 

What does this mean?

Embryos can build everything in the body from scratch, so somewhere in the genome lies the ability to create new tissue. The researchers think that many of these repair genes are present in humans but simply aren't turned on anymore in response to damage. If we can reattach TREE elements to these genes, then perhaps we can resurrect long lost regenerative ability in humans too. 

"We want to find more of these types of elements so we can understand what turns on and ultimately controls the program of regeneration," said Poss. "There may be strong elements that boost expression of the gene much higher than others, or elements that activate genes in a specific cell type that is injured. Having that level of specificity may one day enable us to change a poorly regenerative tissue to a better one with near-surgical precision"

 Read more at MedicalXpress