The zebrafish caudal fin is a powerful model for understanding the cellular and molecular processes underlying regeneration. Following amputation, a proliferative blastema forms, from which all the tissues of the fin regrow. Many aspects of this regenerative process are still poorly understood. For example, what is the source of the various lineages, how do these diverse cell types differentiate in appropriate proportions, and how is their spatial patterning controlled? In two related papers, Nicola Blum and Gerrit Begemann investigate the regeneration of the fin rays, uncovering crucial roles for retinoic acid (RA) signalling – which is known to be important for bone formation during development – at multiple steps of the process.

On p. 2894), the authors uncover a complex series of requirements for active or suppressed RA pathway activity in the bone lineage. RA is known to be synthesized in the blastema immediately following amputation, but the authors find that this inhibits dedifferentiation of osteoblasts to a proliferative preosteoblast state. Subsequently, RA signalling promotes proliferation of the preosteoblasts, then inhibits their differentiation, and is finally required for new bone matrix production. Given these apparently opposing roles for RA at different stages of ray regeneration, levels of the RA-synthesizing enzyme Aldh1a2 and the RA-degrading enzyme Cyp26b1 appear to be tightly regulated in the blastema, in both a spatial and temporal manner.

On p. 2888), Blum and Begemann analyse the role of RA signalling in the spatial control of ray regeneration, such that each ray is separated by an interray region. They find that Cyp26a1 (a paralogue of the blastema-expressed Cyp26b1 discussed above) is expressed in the basal epidermal layer overlying the osteoblasts but absent from the cells overlying the interray tissue. Thus, a low-RA environment exists in the epidermis around the regenerating ray. This permits expression of Sonic hedgehog (Shh), again specifically in the epidermis around the ray, which in turn promotes proliferation of osteoblasts. When this spatial restriction of RA is abolished – using Cyp26a1 inhibitors – osteoblasts spread into the interray regions and the patterning of the regenerating fin is disrupted. Together, these two studies reveal multiple roles for RA in ray regeneration, and highlight the complex signalling dynamics required to achieve efficient and precise regeneration.