RESUMO
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 removed. In the axolotl, appendage amputation initiates a round of wound-associated cell cycle induction followed by continued proliferation that is dependent on nerve-derived signals. 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.
Assuntos
Ambystoma mexicanum/fisiologia , Extremidades/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Regeneração/fisiologia , Ambystoma mexicanum/lesões , Amputação Traumática/metabolismo , Animais , Ciclo Celular/genética , Proliferação de Células/genética , Clonagem Molecular , Extremidades/lesões , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Camundongos , Dados de Sequência Molecular , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/fisiologia , Substrato Quinase C Rico em Alanina Miristoilada , Notophthalmus viridescens/genética , Notophthalmus viridescens/lesões , Notophthalmus viridescens/fisiologia , Cauda/citologia , Cauda/lesões , Cauda/fisiologia , Cicatrização/fisiologia , Xenopus , Peixe-ZebraRESUMO
For over two decades, we have been investigating a strong (ca. 20-100 microA/cm2), outwardly directed electric current driven through the limb stump for the first few days following amputation in regenerating salamanders. This current is driven through the stump in a proximal/distal direction by the amiloride-sensitive transcutaneous voltage of the intact skin of the stump. Limb regeneration can be manipulated by several technique that manipulate this physiology, demonstrating that the ionic current is necessary, but not sufficient, for normal regeneration of the amphibian limb. Here, we demonstrate that a full thickness graft of skin covering the forelimb stump of newts strikingly inhibits the regeneration of the limb, and that this procedure is also highly correlated to a suppression of peak outwardly directed stump currents in those animals that fail to regenerate.
