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In the present study, we hypothesized that EphA4 and one of its potential binding partners EphrinA3 may participate in the inhibition of adult axon regeneration in the model of adult mouse optic nerve injury. Axonal regeneration was analysed in three dimensions after tissue clearing of EphA4 knockout (<jats:styled-content style=\"fixed-case\">KO<\/jats:styled-content>), EphrinA3 <jats:styled-content style=\"fixed-case\">KO<\/jats:styled-content> and wild\u2010type (<jats:styled-content style=\"fixed-case\">WT<\/jats:styled-content>) optic nerves. By immunohistochemistry, EphA4 was highly expressed in M\u00fcller glia endfeet in the retina and in astrocytes in the retina and the optic nerve, while EphrinA3 was present in retinal ganglion cells and oligodendrocytes. Optic nerve crush did not cause expression changes. Significantly more axons grew in the crushed optic nerve of EphA4 <jats:styled-content style=\"fixed-case\">KO<\/jats:styled-content> mice than in <jats:styled-content style=\"fixed-case\">WT<\/jats:styled-content> or EphrinA3 <jats:styled-content style=\"fixed-case\">KO<\/jats:styled-content> animals. Single axon analysis revealed that EphA4 <jats:styled-content style=\"fixed-case\">KO<\/jats:styled-content> axons were less prone to form aberrant branching than axons in the other mouse groups. The expression of growth\u2010associated proteins Sprr1a and Gap\u201043 did not vary between EphA4 <jats:styled-content style=\"fixed-case\">KO<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">WT<\/jats:styled-content> retinae. However, glial fibrillary acidic protein\u2010expressing astrocytes were withdrawn from the perilesional area in EphA4 <jats:styled-content style=\"fixed-case\">KO<\/jats:styled-content>, suggesting that gliosis down\u2010regulation may locally contribute to improve axonal growth at the injury site. In summary, our three\u2010dimensional analysis of injured mouse optic nerves reveals beneficial effects of EphA4 ablation on the intensity and the pattern of optic nerve axon regeneration.<\/jats:p>","DOI":"10.1111\/ejn.12677","type":"journal-article","created":{"date-parts":[[2014,7,15]],"date-time":"2014-07-15T15:31:33Z","timestamp":1405438293000},"page":"3021-3031","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["The Ephrin receptor EphA4 restricts axonal sprouting and enhances branching in the injured mouse optic nerve"],"prefix":"10.1111","volume":"40","author":[{"given":"Sandrine","family":"Joly","sequence":"first","affiliation":[{"name":"Brain Research Institute University of Zurich Winterthurerstrasse 190 Zurich CH\u20108057 Switzerland"},{"name":"Department of Health Sciences and Technology ETH Zurich Zurich 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