Spatiotemporal control of cell cycle acceleration during axolotl spinal cord regeneration
- National Scientific and Technical Research Council (CONICET) and University of La Plata (UNLP), Argentina
- Vienna Biocenter (VBC), Austria
- University of Dundee, United Kingdom
- Technische Universität Dresden, Germany
Abstract
Axolotls are uniquely able to resolve spinal cord injuries, but little is known about the mechanisms underlying spinal cord regeneration. We previously found that tail amputation leads to reactivation of a developmental-like program in spinal cord ependymal cells (Rodrigo Albors et al., 2015), characterized by a high-proliferation zone emerging 4 days post-amputation (Rost et al., 2016). What underlies this spatiotemporal pattern of cell proliferation, however, remained unknown. Here, we use modelling, tightly linked to experimental data, to demonstrate that this regenerative response is consistent with a signal that recruits ependymal cells during ~85 hours after amputation within ~830mm of the injury. We adapted FUCCI technology to axolotls (AxFUCCI) to visualize cell cycles in vivo. AxFUCCI axolotls confirmed the predicted appearance time and size of the injury-induced recruitment zone and revealed cell cycle synchrony between ependymal cells. Our modeling and imaging move us closer to understanding bona fide spinal cord regeneration.
Data availability
Jupyter Notebook (http://jupyter.org/) containing the source code for all computations performed and referred to as Cura Costa et al., 2021 in this study can be found at https://doi.org/10.5281/zenodo.4557840
Article and author information
Author details
Aida Rodrigo Albors
Funding
Agencia Nacional de Promoción Científica y Tecnológica (PICT 2014-3469)
- Osvaldo Chara
Agencia Nacional de Promoción Científica y Tecnológica (PICT 2017-2307)
- Osvaldo Chara
Agencia Nacional de Promoción Científica y Tecnológica (PICT-2019-2019-03828)
- Osvaldo Chara
Consejo Nacional de Investigaciones Científicas y Técnicas (Doctoral Student Fellowship)
- Emanuel Cura Costa
ERC Advanced Grant (742046)
- Elly M Tanaka
Human Frontier Science Program (fellowship LT000785/2019-L.)
- Leo Otsuki
European Union's Horizon 2020 research and innovation programme (Marie Skłodowska-Curie grant agreement No 753812)
- Aida Rodrigo Albors
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: The licenses necessary for work with genetically modified organisms (GMOs) and for experiments specifically involving axolotls (Ambystoma mexicanum) were obtained from the relevant authorities and have been implemented at the IMP in accordance with applicable international, EU and national (Austrian) guidelines.The license for work with GMOs at safety levels 1 and 2 was approved by the GMO office of the Austrian authorities and was issued on 16/03/2017 with no end date (BMGF‐76110/0017‐ II/B/16c/2017).The axolotl research license numbers are GZ: 51072/2019/16 (valid 09/05/2019 - 28/02/2024) and GZ: MA58/665226/2019/21 (valid 24.02.2020 - 30.09.2024). These are approved by the City of Vienna, MA58.There is a dedicated veterinarian for the animal facility, as well as an animal welfare consultant. Animal facility inspections are performed yearly by the City of Vienna, MA58 and the animal licenses and animal husbandry conditions are updated in dialogue with animal welfare authorities.Axolotls (Ambystoma mexicanum) were raised in individual aquaria. Axolotl breedings were performed by the IMP animal facility. All experiments were performed in accordance with locally applicable ethics committee guidelines and within a framework agreed with the Magistrate of Vienna (Austria). Axolotls were anaesthetized with benzocaine (Sigma) diluted in tap water prior to amputation and/or imaging, to minimize suffering.
Copyright
© 2021, Cura Costa 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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Spatiotemporal control of cell cycle acceleration during axolotl spinal cord regeneration
eLife 10:e55665.
https://doi.org/10.7554/eLife.55665
Further reading
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- Cell Biology
- Stem Cells and Regenerative Medicine
Axolotls are uniquely able to mobilize neural stem cells to regenerate all missing regions of the spinal cord. How a neural stem cell under homeostasis converts after injury to a highly regenerative cell remains unknown. Here, we show that during regeneration, axolotl neural stem cells repress neurogenic genes and reactivate a transcriptional program similar to embryonic neuroepithelial cells. This dedifferentiation includes the acquisition of rapid cell cycles, the switch from neurogenic to proliferative divisions, and the re-expression of planar cell polarity (PCP) pathway components. We show that PCP induction is essential to reorient mitotic spindles along the anterior-posterior axis of elongation, and orthogonal to the cell apical-basal axis. Disruption of this property results in premature neurogenesis and halts regeneration. Our findings reveal a key role for PCP in coordinating the morphogenesis of spinal cord outgrowth with the switch from a homeostatic to a regenerative stem cell that restores missing tissue.
