biostudies-literatureOtsuki LEuropean Research Council730-738https://www.ebi.ac.uk/biostudies/studies/S-EPMC12176643biostudies-literatureUnknown642(8068)The amputation of a salamander limb triggers anterior and posterior connective tissue cells to form distinct signalling centres that together fuel regeneration¹. Anterior and posterior identities are established during development and are thought to persist for the whole life in the form of positional memory². However, the molecular basis of positional memory and whether positional memory can be altered remain unknown. Here, we identify a positive-feedback loop that is responsible for posterior identity in the limb of an axolotl (Ambystoma mexicanum). Posterior cells express residual Hand2 transcription factor from development, and this primes them to form a Shh signalling centre after limb amputation. During regeneration, Shh signalling is also upstream of Hand2 exprNatureMolecular basis of positional memory in limb regeneration.PMC12176643742046Falcon FTanaka EMTaniguchi-Sugiura YPlattner SAOtsuki LfalseMolecular basis of positional memory in limb regeneration.The amputation of a salamander limb triggers anterior and posterior connective tissue cells to form distinct signalling centres that together fuel regeneration¹. Anterior and posterior identities are established during development and are thought to persist for the whole life in the form of positional memory². However, the molecular basis of positional memory and whether positional memory can be altered remain unknown. Here, we identify a positive-feedback loop that is responsible for posterior identity in the limb of an axolotl (Ambystoma mexicanum). Posterior cells express residual Hand2 transcription factor from development, and this primes them to form a Shh signalling centre after limb amputation. During regeneration, Shh signalling is also upstream of Hand2 expr2025-01-01T00:00:00Z2025 Jun2026-06-02T02:39:16.665Z2026-04-13T03:12:51.106ZS-EPMC121766434039967710.1038/s41586-025-09036-5