aristaless-like homeobox-3 is wound-induced in muscle and stem cells and is required for planarian head regeneration.

The planarian Schmidtea mediterranea is a well-established model of adult regeneration, which is dependent on a large population of adult stem cells (ASCs) called neoblasts. Upon amputation, planarians undergo transcriptional wounding programs and coordinated stem cell proliferation to give rise to missing tissues. Interestingly, the Wnt signalling pathway is key to guiding what tissues are regenerated, yet less known are the transcriptional regulators that ensure proper activation and timing of signalling pathway components. Here, we identified an aristaless-like homeobox transcription factor, alx-3, enriched in a population of putative neural-fated progenitor cells at homeostasis and is also upregulated in stem cells and muscle at anterior-facing wounds upon amputation. Knockdown of alx-3 results in failure of head regeneration and patterning defects in amputated tail fragments. alx-3 is required for the expression of several early wound-induced genes, including the Wnt inhibitor notum, which is required to establish anterior polarity during regeneration. Together these findings reveal a role for alx-3 as an early wound-response transcriptional regulator in both muscle cells and stem cells that is required for anterior regeneration by promoting a low-Wnt environment.