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The developmental decline in their regenerative ability has been attributed to both intrinsic and extrinsic factors, including postnatal suppression of transcription factors and non\u2010neuronal inhibitory components, respectively. The cell adhesion molecule Contactin 2 (CNTN2) is expressed in neurons and oligodendrocytes in the CNS. Neuronal CNTN2 is highly regulated during development and plays critical roles in axon growth and guidance and neuronal migration. On the other hand, CNTN2 expressed by oligodendrocytes interferes with the myelination process, with its ablation resulting in hypomyelination. In the current study, we investigate the role of CNTN2 in neuronal survival and axon regeneration after trauma, in the murine optic nerve crush (ONC) model. We unveil distinct roles for neuronal and glial CNTN2 in regenerative responses. Surprisingly, our data show a conflicting role of neuronal and glial CNTN2 in axon regeneration. Although glial CNTN2 as well as hypomyelination are dispensable for both neuronal survival and axon regeneration following ONC, the neuronal counterpart comprises a negative regulator of regeneration. Specifically, we reveal a novel mechanism of action for neuronal CNTN2, implicating the inhibition of Akt signalling pathway. The in vitro analysis indicates a BDNF\u2010independent mode of action and biochemical data suggest the implication of the truncated form of TrkB neurotrophin receptor. In conclusion, CNTN2 expressed in CNS neurons serves as an inhibitor of axon regeneration after trauma and its mechanism of action involves the neutralization of Akt\u2010mediated neuroprotective effects.<\/jats:p>","DOI":"10.1111\/ejn.15121","type":"journal-article","created":{"date-parts":[[2021,1,20]],"date-time":"2021-01-20T04:22:22Z","timestamp":1611116542000},"page":"1705-1721","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Neuronal, but not glial, Contactin 2 negatively regulates axon regeneration in the injured adult optic nerve"],"prefix":"10.1111","volume":"53","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9094-1055","authenticated-orcid":false,"given":"Maria","family":"Savvaki","sequence":"first","affiliation":[{"name":"Department of Basic Science Faculty of Medicine University of Crete Crete Greece"},{"name":"Institute of Molecular Biology &amp; Biotechnology \u2010 FoRTH Heraklion, Crete Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"George","family":"Kafetzis","sequence":"additional","affiliation":[{"name":"Department of Biology University of Crete Crete Greece"},{"name":"School of Life Sciences University of Sussex Brighton UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefanos\u2010Ioannis","family":"Kaplanis","sequence":"additional","affiliation":[{"name":"Department of Basic Science Faculty of Medicine University of Crete Crete Greece"},{"name":"Institute of Molecular Biology &amp; 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