Lee Hyun Kyoung, Chaboub Lesley S, Zhu Wenyi, Zollinger Daniel, Rasband Matthew N, Fancy Stephen P J, Deneen Benjamin
Center for Cell and Gene Therapy, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
Center for Cell and Gene Therapy, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA; Program in Developmental Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
Neuron. 2015 Mar 18;85(6):1227-43. doi: 10.1016/j.neuron.2015.02.024. Epub 2015 Mar 5.
Wnt signaling plays an essential role in developmental and regenerative myelination of the CNS; however, contributions of proximal regulators of the Wnt receptor complex to these processes remain undefined. To identify components of the Wnt pathway that regulate these processes, we applied a multifaceted discovery platform and found that Daam2-PIP5K comprise a novel pathway regulating Wnt signaling and myelination. Using dorsal patterning of the chick spinal cord we found that Daam2 promotes Wnt signaling and receptor complex formation through PIP5K-PIP2. Analysis of Daam2 function in oligodendrocytes (OLs) revealed that it suppresses OL differentiation during development, after white matter injury (WMI), and is expressed in human white matter lesions. These findings suggest a pharmacological strategy to inhibit Daam2-PIP5K function, application of which stimulates remyelination after WMI. Put together, our studies integrate information from multiple systems to identify a novel regulatory pathway for Wnt signaling and potential therapeutic target for WMI.
Wnt信号通路在中枢神经系统的发育性和再生性髓鞘形成中起着至关重要的作用；然而，Wnt受体复合物的近端调节因子对这些过程的贡献仍不明确。为了确定调节这些过程的Wnt信号通路的组成部分，我们应用了一个多方面的发现平台，发现Daam2-PIP5K构成了一条调节Wnt信号通路和髓鞘形成的新途径。利用鸡脊髓的背侧模式，我们发现Daam2通过PIP5K-PIP2促进Wnt信号通路和受体复合物的形成。对少突胶质细胞（OLs）中Daam2功能的分析表明，它在发育过程中、白质损伤（WMI）后抑制OL分化，并且在人类白质病变中表达。这些发现提示了一种抑制Daam2-PIP5K功能的药理学策略，应用该策略可刺激WMI后的髓鞘再生。综上所述，我们的研究整合了来自多个系统的信息，以确定Wnt信号通路的一条新的调节途径以及WMI的潜在治疗靶点。
