MARCKS-like protein is an initiating molecule in axolotl appendage regeneration

The salamander, or axolotl, is well known to be able to regenerate missing body parts, but the signals that drive the initial proliferative response were unclear; now, a secreted protein has been identified that induces the initial cell cycle response after injury. The axolotl or Mexican salamander (Ambystoma mexicanum) is remarkable in its ability to regenerate missing body parts. The nature of the signals driving the initial proliferative response that precedes the formation of a blastema responsive to nerve-derived signals has been unclear. Now Elly Tanaka and colleagues have identified a secreted protein — MARCKS-like protein (MLP) — that induces the initial cell cycle response following injury and is necessary for appendage regeneration. How axolotl MLP is delivered extracellularly, and its mode of intracellular signalling remain to be determined. It will be interesting to discover whether MLP orthologues in other species are associated with regeneration. Identifying key molecules that launch regeneration has been a long-sought goal. Multiple regenerative animals show an initial wound-associated proliferative response that transits into sustained proliferation if a considerable portion of the body part has been removed1,2,3. In the axolotl, appendage amputation initiates a round of wound-associated cell cycle induction followed by continued proliferation that is dependent on nerve-derived signals4,5. A wound-associated molecule that triggers the initial proliferative response to launch regeneration has remained obscure. Here, using an expression cloning strategy followed by in vivo gain- and loss-of-function assays, we identified axolotl MARCKS-like protein (MLP) as an extracellularly released factor that induces the initial cell cycle response during axolotl appendage regeneration. The identification of a regeneration-initiating molecule opens the possibility of understanding how to elicit regeneration in other animals.