Abstract
In many organisms, the regenerative capacity of tissues progressively decreases as development progresses. However, the developmental mechanisms that restrict regenerative potential remain unclear. In Drosophila, wing imaginal discs become unable to regenerate upon damage during the third larval stage (L3). Here, we show that production of ecdysone after larvae reach their critical weight (CW) terminates the window of regenerative potential by acting on a bistable loop composed of two antagonistic Broad-complex/Tramtrack/Bric-à-brac Zinc-finger (ZBTB) genes: chinmo and broad (br). Around mid L3, ecdysone signaling silences chinmo and activates br to switch wing epithelial progenitors from a default self-renewing to a differentiation-prone state. Before mid L3, Chinmo promotes a strong regenerative response upon tissue damage. After mid L3, Br installs a nonpermissive state that represses regeneration. Transient down-regulation of ecdysone signaling or Br in late L3 larvae enhances chinmo expression in damaged cells that regain the capacity to regenerate. This work unveils a mechanism that ties the self-renewing and regenerative potential of epithelial progenitors to developmental progression.
Highlights
The impressive ability of some animals to regenerate damaged tissues has fascinated biologists for centuries
While some organisms exhibit remarkable regenerative abilities throughout their life, many animals, including mammals, present limited regenerative potential that progressively decreases during development
We show here that restriction of regenerative potential occurring during midlarval stages is due to the production of a steroid hormone, named ecdysone
Summary
The impressive ability of some animals to regenerate damaged tissues has fascinated biologists for centuries. If ablation is performed during early third larval stage (early L3), ROS and JNK pathway activity elicit activation of the Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) and Wingless (Wg) signaling, leading to a cascade of events triggering regenerative growth and a normal wing in adults. Ectopic feeding of early larvae with ecdysone precociously restricts regenerative capacity [18,19], while preventing ecdysteroid synthesis appears to prolong the capacity to initiate efficient regeneration [20]. In this process, it is still unknown whether ecdysone acts cell-autonomously on wing epithelial tissues or non-cell-autonomously via intermediate signals
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