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One of the enduring debates in regeneration biology is the degree to which regeneration mirrors development. Recent technical advances, such as single-cell transcriptomics and the broad applicability of CRISPR systems, coupled with new model organisms in research, have led to the exploration of this longstanding concept from a broader perspective. In this Review, I outline the historical parallels between development and regeneration before focusing on recent research that highlights how dissecting the divergence between these processes can uncover previously unreported biological mechanisms. Finally, I discuss how these advances position regeneration as a more dynamic and variable process with expanded possibilities for morphogenesis compared with development. Collectively, these insights into mechanisms that orchestrate morphogenesis may reshape our understanding of the evolution of regeneration, reveal hidden biology activated by injury, and offer non-developmental strategies for restoring lost or damaged organs and tissues.
École Polytechnique Fédérale de Lausanne, Foundation Gabriella Giorgi-Cavaglieri, Branco Weiss Fellowship, 407940-206349 Swiss National Science Foundation, Novartis Foundation
Fig. 1. Cell fate differences during development and regeneration exemplified by limb regeneration in two different amphibians. (A) Developing axolotl limb bud with limb bud mesoderm (light green) and apical ectodermal ridge (AER) cells (red). During limb regeneration, axolotl blastema contains cells resembling limb bud mesoderm (dark green), and they do not fully reform AER cells (purple). (B) Developing Xenopus laevis limb bud with AER cells. During limb regeneration, Xenopus reforms AER cells.
Fig. 2. Examples of genetic mutations impacting limb development and regenerative requirements. (A) Fgf10 knockout newts develop malformed limbs, but when these malformed limbs are amputated, they can form normal-looking limbs with digits (Suzuki et al., 2024). (B) Hox13 crispant (mosaic deletion induced by CRISPR) newts develop truncated limbs without a hand; amputation of these limbs results in their regeneration as truncated limbs (Takeuchi et al., 2022). (C) Hand2 crispant axolotls develop normal-looking limbs with four digits (in most cases), but amputation of these limbs results in their regeneration as limbs with fewer digits (Otsuki et al., 2023 preprint).
Fig.3. Dynamic differences between developmental and regenerative processes. (A) Patterning gene expressions for Shh (green) and Fgf8 (blue) in the axolotl, which scale with animal size. (B) Limb development has a fixed growth dynamic and period (t1), whereas limb regeneration growth dynamics depend on amputation position (upper arm amputation has greater growth compared with lower arm amputation). Regardless of amputation position, regeneration completes at a comparable time point (t2). (C) Gene expression programs show greater variability during crustacean Parhyale hawaiensis leg regeneration, whereas such programs have less variability during development (Sinigaglia et al., 2022). Arrows indicate potential gene expression variability
Fig. 4. Regenerative morphogenesis can occur with greater variability compared with development. (A) Development of a limb bud proceeds within a certain range of variability to accomplish morphogenesis. The purple arrow indicates a singular route; the box includes some factors that can alter variability space. (B) Regeneration of a limb operates within a greater variability space. The red arrows indicate that regeneration can initiate different strategies, and the time it takes for regeneration can significantly vary, as shown by the differing arrow lengths. Some of the factors that can influence the variability space are listed in the boxes. Each of these conditions represents an expanded variability compared with the developmental trajectory, setting the variability space in which morphogenesis occurs.
