Summary diagram of regeneration processes. (a) Amputation generates signals that result in histolysis and liberation of cells from their tissue matrix. At the same time, these cells are under hypoxic and endoplasmic reticulum (ER) stress, and use a variety of mechanisms to counter this stress and prevent apoptosis, including upregulation of antiapoptotic pathways that protect cell membranes and nuclei. Some proapoptotic pathways are upregulated but are co-opted to remodel or eliminate internal cell structure. Along with changes in transcription factors, chromatin modifying enzymes, microRNAs and polycomb proteins, these mechanisms lead to dedifferentiation. (b) Throughout histolysis, dedifferentiation and accumulation of blastema cells under the wound epidermis, ecotropic viral integrative factor 5 (EVI5) is highly upregulated, preventing blastema cells from undergoing mitosis until after the accumulation blastema has formed.