CNS regeneration is a diverse and varied trait that is observed in multiple vertebrates. The profile of regenerating species could be consistent with the presence of regeneration in the ancestral vertebrate and loss during evolution.
Anamniotes (that is, lower vertebrates) such as fish and salamanders can undergo not only axon regrowth, but also new neurogenesis after brain and spinal cord injury. Frogs lose this ability around metamorphosis and birds and mammals during embryonic development. Lizards present an intermediate character, with a capacity for extensive neurogenesis in the brain but defective spinal cord regeneration. An important question is whether the loss of regeneration during development in frogs is evolutionarily related to the loss seen in birds and mammals.
Regeneration requires glial cells lining the central lumen to reseal the wound in a way that reconstitutes the stem cell pool for neurogenesis. The profile of glia, their wound-healing ability and the extracellular environment stimulating wound healing has changed over evolution.
Regeneration also depends on glia maintaining and re-accessing expression of embryonic morphogens and their transduction pathways to stimulate cell growth, re-patterning and diversification to regenerate the CNS. Access to these embryonic programmes has become limited in mammals.
Wound healing and regeneration may not be traits that were actively selected for but rather the by-products of a dynamic developmental system of cell interactions, and, in later life stages, the physiology of continued tissue growth.
We speculate that the main selective pressures that have acted on regeneration are how first wounds are healed, and second, whether glial cells can retain access to embryonic genetic programmes to undertake neurogenesis. The latter may have limited CNS complexity in regenerative organisms.
For many years the mammalian CNS has been seen as an organ that is unable to regenerate. However, it was also long known that lower vertebrate species are capable of impressive regeneration of CNS structures. How did this situation arise through evolution? Increasing cellular and molecular understanding of regeneration in different animal species coupled with studies of adult neurogenesis in mammals is providing a basis for addressing this question. Here we compare CNS regeneration among vertebrates and speculate on how this ability may have emerged or been restricted.
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We thank Y. Malashichev, V. Soukup and R. Voss for discussions on evolution. E.M.T. was supported by grants from the Deutsche Forschungsgemeinschaft: SFB655, SPP1356 and TA 274/3-1, and the Bundesministerium für Bildung und Forschung Biofutures. P.F. was suppported by grants from the Biotechnology and Biological Sciences Research Council and the Child Research Appeal Trust.
The authors declare no competing financial interests.
Any multicellular member of the animal kingdom.
A by-product of another essential metazoan trait associated with development, tissue organization or asexual reproduction.
- Blood–brain barrier
A barrier between the blood and the CNS, which is established by specialized capillaries and astrocytes and allows selective entry of compounds from the blood into the CNS parenchyma.
- Glial scar
A barrier composed mainly of reactive astrocytes and proteoglycans that forms after CNS injury to separate healthy from damaged tissues.
- Cellular automata
A method to simulate physical phenomena in space and time by using an array of units (cells) that have certain properties that change according to a given set of rules.
Pigment cells of neural crest origin that, during development, migrate from the neural tube to the skin and other pigmented tissues.
The unit used in taxonomy (classification of plants and animals) to group related plants or animals together at any level of the hierarchy.
A term describing the situation in which embryonic or juvenile characteristics of the ancestor are evident in an adult organism irrespective of the mechanism by which this state came about (encompasses neoteny).
- Selfish junk DNA
DNA elements in the genome that were thought to have no functional role but to self-replicate and multiply within the host genome. Recent work suggests that this non-protein coding DNA contains important regulatory sequences.
A term describing a state whereby the development of a species' somatic body structures has slowed down or is absent, resulting in juvenile traits being present in an adult stage
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Tanaka, E., Ferretti, P. Considering the evolution of regeneration in the central nervous system. Nat Rev Neurosci 10, 713–723 (2009). https://doi.org/10.1038/nrn2707
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