Developmental regulation of regenerative potential in Drosophila by ecdysone through a bistable loop of ZBTB transcription factors

摘要

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. This study finds that the loss of regeneration potential in Drosophila wing imaginal discs is induced by the production of the steroid hormone ecdysone after the larva reaches its critical weight. Manipulating ecdysone signaling or the downstream transcription factors can uncouple regenerative properties from developmental progression. Author summary While some organisms exhibit remarkable regenerative abilities throughout their life, many animals, including mammals, present limited regenerative potential that progressively decreases during development. Understanding the mechanisms underlying this progressive loss is important to devise therapeutic approaches aiming at facilitating the regeneration of a damaged tissue throughout life. The fruitfly Drosophila is a powerful model organism to address such questions. Indeed, while tissues, such as imaginal discs, can fully regenerate if damaged during early development, they fail to do so upon damages during late development. We show here that restriction of regenerative potential occurring during midlarval stages is due to the production of a steroid hormone, named ecdysone. By genetically manipulating ecdysone signaling, we can uncouple regenerative abilities from developmental progression. In particular, we show that ecdysone signaling triggers a switch in the sequential expression of two transcription factors, Chinmo and Broad, that positively and negatively regulate the competence for imaginal disc regeneration, respectively. Our work therefore identifies a key developmental signal that restricts regenerative potential in insects and opens new perspectives on elucidating how regeneration-permissive transcriptional programs are locked as development progresses.