Reactivation of mammalian regeneration by turning on an evolutionarily disabled genetic switch

• 成果类型: Article
• 署名作者: Lin, Weifeng; Jia, Xiaohui; Shi, Xiaofeng; He, Qiuya; Zhang, Panyu; Zhang, Xianglei; Zhang, Liping; Wu, Mingqi; Ren, Tengfei; Liu, Yufei; Deng, Haohao; Li, Yanyao; Liu, Shiqi; Huang, Shaoyong; Kang, Jingmin; Luo, Jun; Deng, Ziqing; Wang, Wei
• 署名单位: National Institute of Biological Sciences, Beijing; Tsinghua University; China Agricultural University; Northwest A&F University - China; Chinese Academy of Medical Sciences - Peking Union Medical College; Peking Union Medical College
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-10505
• DOI: 10.1126/science.adp0176
• 发表日期: 2025-06-26
• 关键词: trans-retinoic acid; tissue regeneration; limb regeneration; zebrafish; stimulation; expression; receptor; skin; fin; cells

摘要

Mammals display prominent diversity in the ability to regenerate damaged ear pinna, but the genetic changes underlying the failure of regeneration remain elusive. We performed comparative single-cell and spatial transcriptomic analyses of rabbits and mice recovering from pinna damage. Insufficient retinoic acid (RA) production, caused by the deficiency of rate-limiting enzyme Aldh1a2 and boosted RA degradation, was responsible for the failure of mouse pinna regeneration. Switching on Aldh1a2 or RA supplementation reactivated regeneration. Evolutionary inactivation of multiple Aldh1a2-linked regulatory elements accounted for the deficient Aldh1a2 expression upon injury in mice and rats. Furthermore, the activation of Aldh1a2 by a single rabbit enhancer was sufficient to improve ear pinna regeneration in transgenic mice. Our study identified a genetic switch involved in the evolution of regeneration.