Neural control of growth and size in the axolotl limb regenerate
- University of Massachusetts Boston, United States
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
Catherine D McCusker
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
- 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
- Received: March 19, 2021
- Preprint posted: April 28, 2021 (view preprint)
- Accepted: November 13, 2021
- Accepted Manuscript published: November 15, 2021 (version 1)
- 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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Neural control of growth and size in the axolotl limb regenerate
eLife 10:e68584.
https://doi.org/10.7554/eLife.68584
Further reading
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Salamanders rely on instructions from the central nervous system when they regenerate their limbs.
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- Developmental Biology
The brain is consisted of diverse neurons arising from a limited number of neural stem cells. Drosophila neural stem cells called neuroblasts (NBs) produces specific neural lineages of various lineage sizes depending on their location in the brain. In the Drosophila visual processing centre - the optic lobes (OLs), medulla NBs derived from the neuroepithelium (NE) give rise to neurons and glia cells of the medulla cortex. The timing and the mechanisms responsible for the cessation of medulla NBs are so far not known. In this study, we show that the termination of medulla NBs during early pupal development is determined by the exhaustion of the NE stem cell pool. Hence, altering NE-NB transition during larval neurogenesis disrupts the timely termination of medulla NBs. Medulla NBs terminate neurogenesis via a combination of apoptosis, terminal symmetric division via Prospero, and a switch to gliogenesis via Glial Cell Missing (Gcm); however, these processes occur independently of each other. We also show that temporal progression of the medulla NBs is mostly not required for their termination. As the Drosophila OL shares a similar mode of division with mammalian neurogenesis, understanding when and how these progenitors cease proliferation during development can have important implications for mammalian brain size determination and regulation of its overall function.
