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The ultrastructure of CNS myelin requires specialized structural myelin proteins, including the transmembrane\u2010tetraspan proteolipid protein (PLP) and the Ig\u2010CAM myelin\u2010associated glycoprotein (MAG). To better understand their functional relevance, we asked to what extent the axon\/myelin\u2010units display similar morphological changes if PLP or MAG are lacking. We thus used focused ion beam\u2010scanning electron microscopy (FIB\u2010SEM) to re\u2010investigate axon\/myelin\u2010units side\u2010by\u2010side in <jats:italic>Plp<\/jats:italic>\u2010 and <jats:italic>Mag<\/jats:italic>\u2010null mutant mice. By three\u2010dimensional reconstruction and morphometric analyses, pathological myelin outfoldings extend up to 10\u00a0\u03bcm longitudinally along myelinated axons in both models. More than half of all assessed outfoldings emerge from internodal myelin. Unexpectedly, three\u2010dimensional reconstructions demonstrated that both models displayed complex axonal pathology underneath the myelin outfoldings, including axonal sprouting. Axonal anastomosing was additionally observed in <jats:italic>Plp<\/jats:italic>\u2010null mutant mice. Importantly, normal\u2010appearing axon\/myelin\u2010units displayed significantly increased axonal diameters in both models according to quantitative assessment of electron micrographs. These results imply that healthy CNS myelin sheaths facilitate normal axonal diameters and shape, a function that is impaired when structural myelin proteins PLP or MAG are lacking.<\/jats:p>","DOI":"10.1002\/glia.24290","type":"journal-article","created":{"date-parts":[[2022,11,10]],"date-time":"2022-11-10T10:04:13Z","timestamp":1668074653000},"page":"509-523","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Focused ion beam\u2010scanning electron microscopy links pathological myelin outfoldings to axonal changes in mice lacking <i>Plp1<\/i> or <i>Mag<\/i>"],"prefix":"10.1002","volume":"71","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4814-7517","authenticated-orcid":false,"given":"Anna M.","family":"Steyer","sequence":"first","affiliation":[{"name":"Department of Neurogenetics Max Planck Institute for Multidisciplinary Sciences  G\u00f6ttingen Germany"},{"name":"Electron Microscopy\u2010City Campus Max 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