Department of Pediatrics and Neurosurgery, Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine and Howard Hughes Medical Institute, University of California, San Francisco, California, USA.
Nat Neurosci. 2011 Jun 26;14(8):1009-16. doi: 10.1038/nn.2855.
Permanent damage to white matter tracts, comprising axons and myelinating oligodendrocytes, is an important component of brain injuries of the newborn that cause cerebral palsy and cognitive disabilities, as well as multiple sclerosis in adults. However, regulatory factors relevant in human developmental myelin disorders and in myelin regeneration are unclear. We found that AXIN2 was expressed in immature oligodendrocyte progenitor cells (OLPs) in white matter lesions of human newborns with neonatal hypoxic-ischemic and gliotic brain damage, as well as in active multiple sclerosis lesions in adults. Axin2 is a target of Wnt transcriptional activation that negatively feeds back on the pathway, promoting β-catenin degradation. We found that Axin2 function was essential for normal kinetics of remyelination. The small molecule inhibitor XAV939, which targets the enzymatic activity of tankyrase, acted to stabilize Axin2 levels in OLPs from brain and spinal cord and accelerated their differentiation and myelination after hypoxic and demyelinating injury. Together, these findings indicate that Axin2 is an essential regulator of remyelination and that it might serve as a pharmacological checkpoint in this process.
白质束的永久性损伤，包括轴突和髓鞘形成的少突胶质细胞，是导致脑瘫和认知障碍的新生儿脑损伤以及成人多发性硬化症的重要组成部分。然而，与人类发育性髓鞘疾病和髓鞘再生相关的调节因子尚不清楚。我们发现，AXIN2 在新生缺氧缺血性和胶质脑损伤的新生儿脑白质病变以及成人多发性硬化症的活动病变中的不成熟少突胶质前体细胞（OLP）中表达。Axin2 是 Wnt 转录激活的靶标，它对该途径起负反馈作用，促进β-catenin 的降解。我们发现 Axin2 功能对于正常的髓鞘再形成动力学是必需的。小分子抑制剂 XAV939 靶向 tankyrase 的酶活性，可稳定脑和脊髓 OLP 中的 Axin2 水平，并加速缺氧和脱髓鞘损伤后的分化和髓鞘形成。总之，这些发现表明 Axin2 是髓鞘再形成的必需调节剂，它可能作为该过程中的药理学检查点。
