Deletion of an enhancer that controls Wnt gene expression following tissue injury produces increased adipogenesis in regenerated muscle.

The capacity to detect and respond to injury is crucial for the recovery and long-term survival of many organisms. Wnts are commonly induced by tissue damage but how they become activated transcriptionally is not well understood. Here, we report that mouse Wnt1 and Wnt10b are induced following injury in both lung and muscle. These Wnts occupy the same chromosome and are transcribed in opposite directions with 12 kb between them. We identified a highly conserved cis-acting regulatory region (enhancer) residing between Wnt1 and Wnt10b that, when fused to a lacZ reporter, is activated post-injury. This enhancer harbors putative AP-1-binding sites that are required for reporter activity, a feature observed in other injury-responsive enhancers. Injured muscles in mice carrying a germline deletion of the enhancer region display reduced Wnt1 and Wnt10b expression and show elevated intramuscular adipogenesis, which can be a hallmark of impaired muscle regeneration or tissue maintenance. Enhancer redundancy is common in development, but our in vivo analysis shows that loss of a single injury-responsive regulatory region in adult tissues can produce a detectable phenotype.