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However, the factors controlling expression of myelin genes in myelination are poorly understood. Here, CXXC5, a recently identified protein with CXXC\u2010type zinc finger DNA binding motif, was characterized as a transcriptional activator of major myelin genes. We identified expression of CXXC5 expression was increased by Wnt\/\u03b2\u2010catenin signaling. CXXC5 specifically expressed in the white matter induced expression of myelin genes through the direct binding of CXXC DNA\u2010binding motif of CXXC5 on the <jats:italic>MBP<\/jats:italic> promoter. During the differentiation of neural stem cells (NSCs) of <jats:italic>CXXC5<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice, the expressions of myelin genes were simultaneously reduced. The <jats:italic>CXXC5<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice exhibited severely reduction of myelin genes expression in corpus callosum as well as abnormalities in myelin structure. The disrupted structural integrity of myelin in the <jats:italic>CXXC5<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice resulted in reduced electrical conduction amplitudes at corpus callosum. These findings indicate that the regulation of myelin genes expression by CXXC5 is important for forming myelin structure involved with axonal electrical signal transfer in the corpus callosum. 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