Reactivating a Genetic Switch Restores Ear Regeneration in Mice

By flipping an evolutionarily disabled genetic switch involved in Vitamin A metabolism, researchers have enabled ear tissue regeneration in mice. Unlike some animals such as fish and salamanders, mammals have limited capacity to regenerate damaged tissues or organs fully.

A variety of strategies have been explored to trigger regeneration in mammals, such as stem cell therapies, gene editing, and electrical stimulation. While these approaches have shown promise, none have fully restored organ function. This is likely due to the biological complexity of mammals and a limited understanding of the genetic factors that govern regenerative abilities. Some mammals, including rabbits, goats, and African spiny mice, can regenerate complex tissues like the ear pinna (the visible outer part of the ear), while others, including common rodents like mice and rats, cannot. Because the ear pinna is a uniquely mammalian structure and varies widely in its ability to regenerate across species, Weifeng Lin and colleagues argue that it makes an ideal model for studying how regenerative capacity has evolved in mammals.

Here, Lin et al. performed a side-by-side comparison between mammal species that can regenerate ear tissue and those that cannot and found that failure of regeneration in nonregenerative species is not due to an inability to form or proliferate the early wound-healing structure known as the blastema. Instead, the key difference lies in how certain wound-induced fibroblasts (WIFs) respond after injury. According to the authors, single-cell RNA sequencing and spatial transcriptomic analyses show that regenerative species activate a gene called Aldh1a2, which is critical for producing Vitamin A or retinoic acid (RA), a signaling molecule essential for regeneration. In nonregenerative species, Aldh1a2 is insufficiently activated due to both reduced expression and enhanced breakdown of RA, which leads to regeneration failure. Notably, Lin et al. discovered that supplying RA externally, or activating Aldh1a2 using a gene enhancer from rabbits, was enough to restore regenerative ability in mice.