1. Evaluation Summary:

    It has long been known that nerves regulate the early formation of the blastema during limb regeneration through the promotion of cell proliferation. The manuscript by Wells-Enright et al. provides an interesting new role for nerves during salamander limb regeneration by showing that nerves also determine how much tissue to regenerate. They demonstrate that increased nerve abundance makes bigger limbs while a decrease in nerve abundance generates smaller limbs. Size regulation of organs is a broadly interesting and clinically important problem, which is why this manuscript should be of interest to a large general audience.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

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  2. Reviewer #1 (Public Review):

    The authors claim that nerves regulate the size of the regenerating limb are convincing and the conclusions justified based upon the results presented. A strength of the manuscript is the clear manipulation of limb size through both gain and loss of function experiments. The major weakness of the manuscript is that mechanism by which nerves regulate limb size is not determined, which leaves an open question on how this phenomenon is regulated. How is it that nerves communicate with cells in the regenerating limb to regulate limb growth?

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  3. Reviewer #2 (Public Review):

    The manuscript by Wells-Enright et al. details an in-depth characterization and experimental analysis of the signals that regulate how relative proportion is interpreted and maintained through an analysis of a regenerating limb model. The work is grounded on classical experimental analysis by Harrison and Twitty in the early 20th century on the regulation of size of limbs during development. Wells-Enright et al. detail distinct phases of regenerative growth 1) blastema stage, incorporating patterning, 2) tiny limb, and late tiny-limb growth in the re-establishment of size comparable to the contralateral limb (not the original size). The growth to the current size of the animal hints that broad-scale systemic signaling (nerve-mediated?) remains a measure of coordination of proportion. The authors further show through elegant experimental approaches that nerves are necessary for late growth, and that relative nerve/tissue ratio is correlated with size and outcomes of experimental analysis. This model would fit with human overgrowth conditions as well. Lastly, the authors use an intriguing new assay in which nerve explants are shown to be sufficient to maintain growth of a regenerate. However, the authors find that these explants, when removed from the normal area of function, do not provide specific information as to size.

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