Understanding a tissue's ability to regenerate
Regeneration occurs in many organisms, and in a variety of tissues. While diverse examples of regeneration exist, a common theme is that regenerative capacity can change with time, often becoming increasingly limited as development proceeds. The embryonic mouse heart, for example, shows a remarkable ability to regenerate, able to replace up to 50% of diseased tissue before birth1. Subsequently, this regenerative ability is limited to the first week of neonatal life, as the regenerative response is instead replaced by scar formation and permanent loss of functional tissue in older animals2. This age-related decline of regenerative ability is widespread, observed in mice2, 3, amphibians4, invertebrates5 and humans6. Even teleost fish (including Zebrafish), which are thought to have an almost unlimited ability to regenerate numerous tissues, show some decline in regenerative ability with age7. Understanding the mechanisms that dictate changes in regenerative capacity is vital for developing methods to stimulate or enhance regeneration. However, the underlying cellular and genetic events that lead to changes in regenerative capacity are still very much unexplored.
Our research is investigating a fundamental yet unresolved aspect of regeneration: What are the underlying genetic mechanisms that cause a tissue’s regenerative response to diminish over time?
Tissues often regenerate better following damage in developmentally younger organisms vs. those at an older stage. Understanding why will enable us to develop ways to improve or stimulate regeneration in non-regenerating tissues.
Our lab is investigating why a tissue loses regenerative capacity at the genetic level, using the fruit fly Drosophila melanogaster. Our work takes advantage of the wing imaginal disc, an epithelial tissue in the larva that forms the adult wing after pupariation. The extensive characterization of its growth and patterning, and the availability of many genetic and biological reagents, makes the wing disc highly conducive to developmental research.
We use the imaginal discs of Drosophila to study regeneration. They are the larval precursors organs, which grow during larval life and differentiate into adult structures such as the wing or leg during pupariation. These larval tissues have a remarkable ability to regenerate following various types of damage including physical injury, irradiation or genetic ablation. Importantly, they lose this ability as larvae mature, making them an ideal platform to study the loss of regenerative ability.
The wing imaginal is the largest of the discs, and forms the body wall, the hinge and the wing blade of the adult fly. The tissue consists of a columnar epithelium, the disc proper, and a layer of squamous cells, the peripodial epithelium. If the disc is damaged, the degree of regeneration can be assayed by looking at the size and patterning of the resulting adult wing.
Our research has revealed the existence of a previously undescribed mechanism that controls the expression of genes involved in a regenerative response. We have characterized a damage-activated region of the genome that, when activated by injury, leads to the expression of two flanking genes, WNT1 (wg) and WNT6. This Damage-Activated Regeneration Enhancer or DARE induces expression of these genes only upon damage in younger tissues. As the tissue matures, the enhancer region becomes progressively inactivated by the accumulation of epigenetic silencing modifications. Importantly, this mechanism still permits developmental enhancers to shape expression of both genes in undamaged tissues.
In younger tissues (top), signals created by injury lead to the expression of the WNT genes, Wg and WNT6, via the Damage-Activated Regeneration Enhancer, "DARE" , shown in blue. In older tissue (bottom), this same region becomes epigenetically silenced (orange), preventing damage induced signals from activating regenerative gene expression, but still permitting normal developmentally regulated WNT expression in undamaged tissues from nearby developmentally regulated enhancers (green).
We have evidence that this mechanism doesn't just regulate the expression of the two WNT genes, but may also control the expression of many other genes required for regeneration, and thus it could be a widespread mechanism that permits control over both activation and age-related silencing of an entire regeneration program. A comprehensive understanding of this mechanism has the potential to lead to methods to activate regeneration in any injured tissue.
In our lab we have several projects aimed at understanding this mechanism, and the genes it may control.