show Abstracthide AbstractRegeneration is a widespread phenomenon that often requires formation of a new tissue outgrowth at wounds called a blastema. Identifying the key signals that trigger blastema formation is therefore fundamental for understanding the mechanistic basis of regeneration. We uncovered a role for the wound epidermis in regeneration initiation in planarians. The gene equinox is expressed within hours of injury in the planarian wound epidermis and encodes a secreted protein conserved in many phyla. Following equinox inhibition, animals failed to form blastemas, reset positional information, and upregulate stem cell (neoblast) proliferation at wounds. Associated with these defects was an inability to maintain wound-induced gene expression. We propose that activation of equinox in the wound epidermis initiates planarian regeneration. Overall design: Polyadenylated RNA was isolated from post-pharyngeal fragments at 0, 3, 6, 16, 24, and 48 hours post-amputation (hpa) from planarians following RNAi of a control gene (C.elegans unc-22; 5 replicates) and bmp4 (5 replicates). Worms were fed four times over two weeks, and cut 7 days after 4th feeding.