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While only Gas6 directly activates Axl, ProS1 activation of Tyro3\/MerTK can indirectly activate Axl through receptor heterodimerization. Therefore, we generated Gas6<jats:sup>\u2013\/\u2013<\/jats:sup>Axl<jats:sup>\u2013\/\u2013<\/jats:sup> double knockout (DKO) mice to specifically examine the contribution of this signaling axis while retaining ProS1 signaling through Tyro3 and MerTK. We found that na\u00efve young adult DKO and WT mice have comparable myelination and equal numbers of axons and oligodendrocytes in the corpus callosum. Using the cuprizone model of demyelination\/remyelination, transmission electron microscopy revealed extensive axonal swellings containing autophagolysosomes and multivesicular bodies, and fewer myelinated axons in brains of DKO mice at 3\u2010weeks recovery from a 6\u2010week cuprizone diet. Analysis of immunofluorescent staining demonstrated more SMI32+ and APP+ axons and less myelin in the DKO mice. There were no significant differences in the number of GFAP+ astrocytes or Iba1+ microglia\/macrophages between the groups of mice. However, at 6\u2010weeks cuprizone and recovery, DKO mice had increased proinflammatory cytokine and altered suppressor of cytokine signaling (SOCS) mRNA expression supporting a role for Gas6\u2010Axl signaling in proinflammatory cytokine suppression. Significant motor deficits in DKO mice relative to WT mice on cuprizone were also observed. These data suggest that Gas6\u2010Axl signaling plays an important role in maintaining axonal integrity and regulating and reducing CNS inflammation that cannot be compensated for by ProS1\/Tyro3\/MerTK signaling.<\/jats:p>","DOI":"10.1002\/glia.23214","type":"journal-article","created":{"date-parts":[[2017,9,19]],"date-time":"2017-09-19T06:08:46Z","timestamp":1505801326000},"page":"2051-2069","source":"Crossref","is-referenced-by-count":68,"title":["Loss of <scp>G<\/scp>as6 and <scp>A<\/scp>xl signaling results in extensive axonal damage, motor deficits, prolonged neuroinflammation, and less remyelination following cuprizone exposure"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5760-7821","authenticated-orcid":false,"given":"Alex K.","family":"Ray","sequence":"first","affiliation":[{"name":"Department of Pathology, Albert Einstein College of Medicine Montefiore Medical Center, Bronx  New York 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