. Robust Axonal Regeneration Occurs in the Injured CAST/Ei Mouse CNS. Neuron. 2015 May 20; PubMed.

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  1. Unlike the axons in the peripheral nervous system, the axons in the central nervous system do not readily regenerate after injury. In this study by Omura et al., the investigators have screened several different mouse strains and discovered that one strain, namely the CAST/Ei, shows exceptional regenerative phenotypes. Furthermore, the investigators carried out a series of experiments to examine what genes/proteins are differentially expressed in the CAST/Ei mice, and revealed that a protein called Activin is particularly active, and is responsible for the remarkable axon regeneration in these animals.

    Interestingly, this protein is known to regulate tissue regeneration in lower-vertebrate species such as fish and gecko. While some studies in the past have indicated differential regenerative and cell survival capacities among different mouse strains, this current study went the distance and performed comprehensive analyses, revealing key growth regulators. Given that the lack of axon regeneration/plasticity poses great challenges to the healing of neurodegenerative conditions including ALS, and CNS trauma (e.g., spinal cord injury), uncovering such mouse strains and proteins will help us further understand mechanisms controlling this process, and ultimately develop therapies.

    View all comments by Kevin Park
  2. Thanks, Kevin, for the encouraging words in summarizing this article. We are thrilled with the amount of regeneration observed in the CAST animals, and also that the molecular mechanisms we identify parallel those in lower species that can readily regenerate body parts. We are confident that this is a major discovery in the field of CNS regenerative medicine. We plan to continue to develop these mechanisms and hope that others also attempt to elucidate the keys that this mouse strain offers us toward achieving sustained effective axonal growth in the CNS. Clearly our aim in unraveling these mechanisms is to one day allow therapies for patients with neurodegenerative conditions in the CNS.

    View all comments by Michael Costigan
  3. First, I want to congratulate Dr. Cliff Woolf, his colleagues and collaborators for this beautifully executed study in Neuron. Speaking as someone who was trained as a mouse geneticist, the current work is a tour de force, using the power of mouse genetics to identify new genes that regulate an important biological process. Scientists have long suspected - and even had some fragmentary evidence - that different mouse strains have different regenerative abilities and that this is a trait that can be traced to discover new genes to promote axon regeneration. However, to my knowledge, the current study is the first of its kind to bring this idea to fruition.

    What is particularly impressive here is that a single gene was identified as a major contributor to the high regenerative ability of Mus musculus castaneus. In retrospect, the inclusion of castaneus was crucial to the success of the project. For ease of handling, castaneus may not have been an obvious choice. These mice are not easy to work with: they try to jump out of the cage at any instance. However, casteneus is genetically divergent from common laboratory mouse strains and the high level of polymorphisms between the two has been employed to facilitate genetic mapping studies. This was probably the original plan and it would have taken years just to finish the mapping, let alone identify new genes. Instead, Woolf and colleagues took advantage of new tools in genomics in their search for candidate genes. Gene expression profiling allowed them to quickly narrow a list of candidate regenerative genes down to just over a dozen genes, with one (Inhba, which encodes Inhibin beta A, a subunit of Activin as well as Inhibin) topping the list. Pharmacological experiments showed the functional relevance of this molecule.

    In an ideal world, one would also like to test the function of Inhba by conditionally deleting the gene in castaneus. However, that would simply be too much to ask for in this case, given the tremendous amount of work already done by the researchers. In fact, if an assistant professor were to start a lab with this project, he/she would likely run out of funding before a tenure decision is made. The repertoire of expertise involved in this study is unparalleled by any other in neural regeneration research - the long list of authors, including many recognized scientists, is a testimony to this fact.

    In the end, we learned that Activin is a new important player in CNS axon regeneration, especially under conditions that prime the neurons for regeneration. We are reaffirmed - more strongly than ever - that mouse genetics has a place in neural regeneration research, and that classical mouse genetics can be combined with modern genomic tools to speed up discoveries even for something as seemingly intractable as regeneration in the brain and spinal cord.

    View all comments by Binhai Zheng

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