Regeneration is widespread, but mechanisms that activate regeneration remain mysterious. Planarians are capable of whole-body regeneration and mount distinct molecular responses to wounds that result in tissue absence and those that do not. A major question is how these distinct responses are activated. We describe a follistatin homolog (Smed-follistatin) required for planarian regeneration. Smed-follistatin inhibition blocks responses to tissue absence but does not prevent normal tissue turnover. Two activin homologs (Smed-activin-1 and Smed-activin-2) are required for the Smed-follistatin phenotype. Finally, Smed-follistatin is wound-induced and expressed at higher levels following injuries that cause tissue absence. These data suggest that Smed-follistatin inhibits Smed-Activin proteins to trigger regeneration specifically following injuries involving tissue absence and identify a mechanism critical for regeneration initiation, a process important across the animal kingdom.
Most animals can respond to injury with some form of tissue regeneration. In mammals, this is limited to wound healing, whereas other vertebrates—such as salamanders and zebrafish—can regenerate parts of internal organs and even entire appendages. The planarian, a flatworm, is even more remarkable, being able to regenerate its head or tail following amputation, and even a whole animal from just a small body fragment. This is particularly impressive given that planarians have a complex internal anatomy, which includes muscles, intestines, a system similar to kidneys, and a central nervous system with a brain.
How is such regeneration accomplished? Why are planarians able to regenerate their bodies so extensively, whereas humans cannot? To what extent are the mechanisms of planarian regeneration common to other animals? These questions have driven the study of planarian regeneration for more than a century, but it is only in recent years that the tools needed to address these questions at the molecular level have become available.
Planarian regeneration proceeds over several days and involves multiple processes, including gene expression, cell division and cell death. Importantly, it has recently been shown that planarians activate different responses depending on whether an injury results in significant tissue loss—and therefore requires regeneration for repair—or if simple wound healing will be sufficient. The mechanisms behind these different responses to injury have, however, remained a mystery.
Now, Gaviño et al. have identified a key mechanism in the initiation of regeneration following tissue loss. This is centered on the gene follistatin, which is expressed following wounding. When genetic techniques are used to disrupt the expression of follistatin, regeneration is completely blocked. However, the animal’s ability to routinely replace old cells via a stem-cell mediated mechanism is unaffected. This indicates that follistatin is specifically required for the replacement of cells lost through injury. Gaviño et al. further demonstrate that the protein encoded by follistatin likely initiates tissue regeneration upon substantial tissue loss through inhibition of proteins called Activins.
Activin and Follistatin proteins are broadly conserved in evolution, and are also expressed in mammals, raising the possibility that similar molecular circuits may govern regenerative responses in many species.