Apcdd1 stimulates oligodendrocyte differentiation after white matter injury.
Apcdd1 stimulates oligodendrocyte differentiation after white matter injury.
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作者：
Lee HK;Laug D;Zhu W;Patel JM;Ung K;Arenkiel BR;Fancy SP;Mohila C;Deneen B
WNT信号在中枢神经系统的发育和再生髓鞘形成中起着至关重要的作用，因此了解与这一复杂途径的各个调节层相关的因素如何参与这些过程是至关重要的。近年来，Apcdd1被认为是近端Wnt信号的负调控因子，但其在中枢神经系统少突胶质细胞(OL)分化和抑制中的作用尚不清楚。对Apcdd1表达的分析表明，Apcdd1在OL发育过程中动态表达，在分化过程中表达上调。利用体外和体外OL系统进行的功能研究表明，Apcdd1促进OL分化，抑制Wnt信号，并与β-catenin结合。将这些发现应用于白质损伤(WMI)模型显示，Apcdd1类似地促进了体内胶质毒性损伤和体外急性缺氧后的OL分化。检测新生儿WMI和成人多发性硬化症患者脑白质病变中Apcdd1的表达，发现其在少突胶质细胞前体细胞亚群中表达。这些研究首次描述了Apcdd1在WMI后OLS中的作用，并揭示了Wnt途径近端的负调控因子可以影响再生髓鞘形成，为调节Wnt信号和刺激WMI后的修复提供了一种新的治疗策略。
Wnt signaling plays an essential role in developmental and regenerative myelination of the CNS, therefore it is critical to understand how the factors associated with the various regulatory layers of this complex pathway contribute to these processes. Recently, Apcdd1 was identified as a negative regulator of proximal Wnt signaling, however its role in oligodendrodcyte (OL) differentiation and reymelination in the CNS remain undefined. Analysis of Apcdd1 expression revealed dynamic expression during OL development, where its expression is upregulated during differentiation. Functional studies using ex vivo and in vitro OL systems, revealed that Apcdd1 promotes OL differentiation, suppresses Wnt signaling, and associates with β-catenin. Application of these findings to white matter injury (WMI) models revealed that Apcdd1 similarly promotes OL differentiation after gliotoxic injury in vivo and acute hypoxia ex vivo. Examination of Apcdd1 expression in white matter lesions from neonatal WMI and adult Multiple Sclerosis revealed its expression in subsets of oligodendrocyte precursors. These studies describe, for the first time, the role of Apcdd1 in OLs after WMI and reveal that negative regulators of the proximal Wnt pathway can influence regenerative myelination, suggesting a new therapeutic strategy for modulating Wnt signaling and stimulating repair after WMI.