Overview

• The transcription factor Hand2 has been identified as the critical positional cue that activates Sonic hedgehog (Shh) signaling during axolotl limb regeneration.
• Hand2 expression is upregulated upon injury, triggering a signaling cascade that ensures precise limb patterning and regrowth.
• Transplantation experiments demonstrated that Shh signaling can reprogram cells to adopt new positional identities, supporting a flexible 'radio broadcast' model of regeneration.
• The Hand2-Shh-FGF8 signaling loop, conserved across vertebrates, offers promising pathways for advancing tissue engineering and regenerative therapies in humans.
• This breakthrough was made possible by new genetic and cell-tracing tools, overcoming challenges posed by the axolotl's large and complex genome.