One reason why we know relatively little about the biological basis of complex tissue regeneration is that it has been traditionally studied in vertebrate organisms — such as the newt — for which genetic tools are not available. Kenneth Poss and colleagues now suggest a solution to this problem: zebrafish. These fish can regenerate an impressive number of adult structures, from fins to spinal cord. Combine this with their genetic tractability, and you have the ideal vertebrate organism in which to study regeneration, as Poss et al. illustrate with their recent findings.

To investigate the genetic basis of fin regeneration, the authors mutagenized zebrafish with ENU and then screened the parthenogenetic offspring of F1 females for temperature-sensitive defects in caudal fin regeneration. A temperature-sensitive screen was chosen because many of the genes that are involved in regeneration are probably also required for embryogenesis. The mutant they recovered — nightcap (ncp) — underwent normal fin regeneration at 25 °C but not at 33 °C. At this temperature, fin regeneration stalled two days post-amputation, with the mesenchymal cells that form the proximal part of the blastema showing morphological abnormalities. This part of the blastema — which forms at the wound and from which the new fin arises — is highly proliferative and is believed to drive regeneration.

Through positional cloning, Poss et al. next identified the genetic defect that underlies ncp — a point mutation in a highly conserved kinase domain of the mps1 gene. Mps1 is known to function in cell division and in mitotic checkpoint signalling in organisms ranging from yeast to mice. That this mutation underlies the ncp mutant phenotype was further strengthened by the authors' findings of mitotic checkpoint defects in ncp embryonic cells. Moreover, mps1 expression is undetectable in adult caudal fins, but becomes upregulated 18–24 hours following fin amputation and soon localizes to a subpopulation of cells in the proximal blastema. Mitotic analyses showed that — two days after amputation — these cells undergo around one-fifth of the number of mitoses in ncp mutants as they do in wild-type fin blastemas.

Together, these findings shed new light on the role of the proximal blastema in zebrafish fin regeneration and on the function of mps1 in the proliferative activity of this tissue. Importantly, they also show the power of zebrafish genetics for investigating the genetic basis of complex tissue regeneration and how conditional zebrafish regeneration mutants can be used to study genes that might also be essential for embryonic development.