Abstract

The mechanisms that regulate growth and size of the regenerating limb in tetrapods such as the Mexican axolotl are unknown. Upon the completion of the developmental stages of regeneration, when the regenerative organ known as the blastema completes patterning and differentiation, the limb regenerate is proportionally small in size. It then undergoes a phase of regeneration that we have called the 'tiny-limb' stage, that is defined by rapid growth until the regenerate reaches the proportionally appropriate size. In the current study we have characterized this growth and have found that signaling from the limb nerves is required for its maintenance. Using the regenerative assay known as the Accessory Limb Model, we have found that growth and size of the limb positively correlates with nerve abundance. We have additionally developed a new regenerative assay called the Neural Modified-ALM (NM-ALM), which decouples the source of the nerves from the regenerating host environment. Using the NM-ALM we discovered that non-neural extrinsic factors from differently sized host animals do not play a prominent role in determining the size of the regenerating limb. We have also discovered that the regulation of limb size is not autonomously regulated by the limb nerves. Together, these observations show that the limb nerves provide essential cues to regulate ontogenetic allometric growth and the final size of the regenerating limb.

Data availability

The raw data used to generate the figures for this paper are available in the source data files corresponding to that figure.

Article and author information

Author details

  1. Kaylee M Wells

    Biology Department, University of Massachusetts Boston, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Kristina Kelley

    Biology Department, University of Massachusetts Boston, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Mary Baumel

    Biology Department, University of Massachusetts Boston, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8551-4785
  4. Warren A Vieira

    Biology Department, University of Massachusetts Boston, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Catherine D McCusker

    Biology, University of Massachusetts Boston, Boston, United States
    For correspondence
    catherine.mccusker@umb.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0127-433X

Funding

National Institutes of Health (0R15HD092180-01A1)

  • Catherine D McCusker

University of Massachusetts Boston (Doctoral Dissertation Grant)

  • Kaylee M Wells

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. K VijayRaghavan, National Centre for Biological Sciences, Tata Institute of Fundamental Research, India

Ethics

Animal experimentation: This study was carried out in accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The experimental work was approved by the Institutional Animal Care and Use Committee of the University of Massachusetts Boston; protocol number IACUC2015004, animal welfare assurance number D16-00246 (A3383-01).

Version history

  1. Received: March 19, 2021
  2. Preprint posted: April 28, 2021 (view preprint)
  3. Accepted: November 13, 2021
  4. Accepted Manuscript published: November 15, 2021 (version 1)
  5. Version of Record published: December 29, 2021 (version 2)

Copyright

© 2021, Wells et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Kaylee M Wells
  2. Kristina Kelley
  3. Mary Baumel
  4. Warren A Vieira
  5. Catherine D McCusker
(2021)
Neural control of growth and size in the axolotl limb regenerate
eLife 10:e68584.
https://doi.org/10.7554/eLife.68584

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https://doi.org/10.7554/eLife.68584

Further reading

  1. Salamanders rely on instructions from the central nervous system when they regenerate their limbs.

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