Abstract
Axolotls are unique in their ability to regenerate the spinal cord. However, the mechanisms that underlie this phenomenon remain poorly understood. Previously, we showed that regenerating stem cells in the axolotl spinal cord revert to a molecular state resembling embryonic neuroepithelial cells and functionally acquire rapid proliferative divisions (Rodrigo Albors et al., 2015). Here, we refine the analysis of cell proliferation in space and time and identify a high-proliferation zone in the regenerating spinal cord that shifts posteriorly over time. By tracking sparsely-labeled cells, we also quantify cell influx into the regenerate. Taking a mathematical modeling approach, we integrate these quantitative datasets of cell proliferation, neural stem cell activation and cell influx, to predict regenerative tissue outgrowth. Our model shows that while cell influx and neural stem cell activation play a minor role, the acceleration of the cell cycle is the major driver of regenerative spinal cord outgrowth in axolotls.
Highlights
Neural stem cells exist in the spinal cord of all vertebrates, but only in salamanders these cells are mobilized efficiently to resolve spinal cord injuries (Becker and Becker, 2015; Tanaka and Ferretti, 2009)
There, we found that resident SOX2+ neural stem cells re-activate an embryonic-like gene expression program following tail amputation (Rodrigo Albors et al, 2015)
Part of this program involves the re-establishment of planar cell polarity (PCP) signaling, the downregulation of pro-neural genes, and upregulation of proliferation-promoting genes. In line with these gene expression changes, we found that regenerating neural stem cells speed up their cell cycle, and switch from neuron-generating to proliferative cell divisions
Summary
Neural stem cells exist in the spinal cord of all vertebrates, but only in salamanders these cells are mobilized efficiently to resolve spinal cord injuries (Becker and Becker, 2015; Tanaka and Ferretti, 2009) In axolotls, this is best exemplified following tail amputation, when cells adjacent to the cut end regrow a fully functional spinal cord (Holtzer, 1956; Mchedlishvili et al, 2007). There, we found that resident SOX2+ neural stem cells re-activate an embryonic-like gene expression program following tail amputation (Rodrigo Albors et al, 2015) Part of this program involves the re-establishment of planar cell polarity (PCP) signaling, the downregulation of pro-neural genes, and upregulation of proliferation-promoting genes. Besides oriented cell division, whether other cellular mechanisms such as convergence and
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