Conserved anterior/posterior tissue asymmetry encodes proximal/distal positional information during axolotl limb regeneration

This asymmetric A/P boundary aligns with the expression of AP-1 complex components and ERK signaling activation previously shown to be distally enriched in developing embryonic limb buds. Treatment of blastemas in different limb positions with an ERK inhibitor shows that ERK signaling is an upstream modulator of both distal and posterior limb patterning genes, linking the asymmetric A/P boundary with the Pr/Di positioning of the blastema along the limb axis.

These findings challenge the long-standing model of a symmetrical A/P midline boundary in limbs, offering clarity to findings that previously were incongruent with the midline boundary model. Here, we propose a revised asymmetric boundary model, in which shifting A/P ratios regulates Pr/Di patterning. Remarkably, this same pattern is observed in fetal human limbs, revealing a new, evolutionarily conserved paradigm for developmental and regenerative limb patterning.