Tissue Regeneration Study Learns From Salamanders
September 26, 2012

Tissue Regeneration Research Turns to Salamander Genome For Clues

Connie K. Ho for redOrbit.com — Your Universe Online

Researchers from the Salk Institute recently studied the regeneration of new limbs in salamanders and believe that the findings could be useful in studies on regenerative medicine for humans.

The scientists published two different studies on the Mexican axolotl, a species of aquatic salamander that has lizard-like characteristics. They found that the salamanders needed more than just the activation of genes in order to jumpstart the limb-regeneration process.

The team looked at several so-called “jumping genes” and determined that they had to be repressed, otherwise they would migrate around in the genomes of cells in the tissue that was to become the new limb, thus interfering with the regeneration process.

Jumping genes — also known as transposable elements (TEs) — are sequences of DNA that can be “cut and pasted” or “copy and pasted” to other parts of an organisms genome.

One study was published in the August 23 edition of Development, Growth & Differentiation and the other in the July 27 edition of Developmental Biology.

"What our work suggests is that jumping genes would be an issue in any situation where you wanted to turn on regeneration," explained senior author Tony Hunter, a professor in the Molecular and Cell Biology Laboratory and director of the Salk Institute Cancer Center, in a prepared statement.

In the study, the researchers discovered that two proteins called piwi-like 1 (PL1) and piwi-like 2 (PL2) were able to help halt the movement of the jumping genes in the tadpole-like form of the salamander.

"As complex as it already seems, it might seem a hopeless task to try to regenerate a limb or body part in humans, especially since we don't know if humans even have all the genes necessary for regeneration," continued Hunter in the statement.

"For this reason, it is important to understand how regeneration works at a molecular level in a vertebrate that can regenerate as a first step. What we learn may eventually lead to new methods for treating human conditions, such as wound healing and regeneration of simple tissues."

The scientists worked together to characterize the transcriptional fingerprint taken from the earlier periods of axolotl regeneration and focused specifically on their blastema, a structure that develops at the stump of the limb that is to be regenerated.

By studying the formation of blastema, the team of investigators was able to identify transcriptional activation at some genes, a process that for most animals only takes place in germline cells like sperm or eggs. The findings showed that there was cellular reprogramming of differentiated cells occurring in the animal.

The study published in Development, Growth & Differentiation looked at the long interspersed nucleotide element-1 (LINE-1) retrotransposon. LINE-1 elements are related to early vertebrate evolution and are pieces of DNA that copy in two stages, once from DNA to RNA by transcription and again from RNA to DNA by reverse transcription.

The copies of the DNA are then inserted into the cell´s genome. The LINE-1 retrotransposons were found to be continuously jumping. A past study from the Salk Institute also found that the LINE-1 elements will move during neuronal development and could possibly program the identities of individual neurons.

"Most of these copies appear to be 'junk' DNA, because they are defective and can never jump again," commented Hunter in the statement.

In the study, PL1 and PL2 were found to switch off the transcription of repeat elements like LINE-1.

"The idea is that in the development of germ cells, you definitely don't want these things hopping around," noted Hunter in the statement. "The mobilization of these jumping genes can introduce harmful genomic rearrangements or even abort the regeneration process."

When the researchers inhibited PL1 and PL2 activity, they saw that the rate of regeneration was slower.

"The need to switch on one set of genes to stop other genes from jumping just illustrates how amazingly difficult it would be to regenerate something as complex as a limb in humans," concluded Hunter in the statement. "But that doesn't mean we won't learn valuable lessons about how to treat degenerative diseases."