Signaling pathways that promote oligodendrocyte development improve oligodendrocyte regeneration and myelin recovery from demyelinating pathologies. Sox factors critically control myelin gene expression and oligodendroglial fate, but little is known about signaling events underlying Sox-mediated oligodendroglial regeneration. In this study of the SoxF member Sox17, we demonstrate that Sox17-induced oligodendrocyte regeneration in adult myelin lesions occurs by suppressing lesion-induced Wnt/beta-catenin signaling which is inhibitory to oligodendrocyte regeneration and by increasing Sonic Hedgehog/Smoothened/Gli2 activity. Hedgehog signaling through Smoothened critically supports adult oligodendroglial viability and is an upstream regulator of beta-catenin. Gli2 ablation in adult oligodendrocyte progenitor cells indicates that Gli2 regulates beta-catenin differentially in wild-type and Sox17-overexpressing white matter. Myelin lesions in Sox17-deficient mice show beta-catenin hyperactivation, regenerative failure, and loss of oligodendrogenesis, despite exogenous Hedgehog stimulation. These studies indicate the benefit of Sox17 signaling targets to enhance oligodendrocyte regeneration after demyelination injury by modulating both Hedgehog and Wnt/beta-catenin signaling.

促进少突胶质细胞发育的信号通路可改善少突胶质细胞再生和髓鞘从脱髓鞘病变中的恢复。索克斯因子关键地控制髓磷脂基因表达和少突胶质细胞命运，但对有关索克斯介导的少突胶质细胞再生的信号传递事件知之甚少。在SoxF成员Sox17的这项研究中，我们证明了成年髓鞘病变中Sox17诱导的少突胶质细胞再生是通过抑制病变诱导的Wnt /β-catenin信号传导而发生的，该信号抑制少突胶质细胞的再生并通过增加Sonic Hedgehog / Smoothened / Gli2活性。通过“平滑化”实现的刺猬信号可关键支持成人少突胶质细胞的生存能力，并且是β-catenin的上游调节剂。成年少突胶质细胞祖细胞中的Gli2消融表明，Gli2在野生型和过表达Sox17的白质中差异调节β-catenin。尽管有外源的刺猬刺激，但Sox17缺陷型小鼠的髓磷脂损伤表现出β-catenin过度活化，再生衰竭和少突胶质生成的损失。这些研究表明，Sox17信号转导靶标可通过调节刺猬和Wnt /β-catenin信号转导来促进脱髓鞘损伤后少突胶质细胞的再生。