Wang Chih-Yen, Zuo Zhongyuan, Kim Kyoung In, Bellen Hugo J, Lee Hyun Kyoung
bioRxiv. 2023 Apr 11:2023.04.11.536369. doi: 10.1101/2023.04.11.536369.
Wnt signaling plays an essential role in developmental and regenerative myelination in the CNS. The Wnt signaling pathway is comprised of multiple regulatory layers; thus, how these processes are coordinated to orchestrate oligodendrocyte development remains unclear. Here we show CK2α, a Wnt/β-catenin signaling Ser/Thr kinase, phosphorylates Daam2, inhibiting its function and Wnt-activity during oligodendrocyte development. Intriguingly, we found Daam2 phosphorylation differentially impacts distinct stages of oligodendrocyte development, accelerating early differentiation followed by decelerating maturation and myelination. Application towards white matter injury revealed CK2α-mediated Daam2 phosphorylation plays a protective role for developmental and behavioral recovery after neonatal hypoxia, while promoting myelin repair following adult demyelination. Together, our findings identify a novel regulatory node in the Wnt pathway that regulates oligodendrocyte development via protein phosphorylation-induced signaling complex instability and highlights a new biological mechanism for myelin restoration.
Wnt signaling plays a vital role in OL development and has been implicated as an adverse event for myelin repair after white matter injury. Emerging studies have shed light on multi-modal roles of Wnt effectors in the OL lineage, but the underlying molecular mechanisms and modifiable targets in OL remyelination remain unclear. Using genetic mouse development and injury model systems, we delineate a novel stage-specific function of Daam2 in Wnt signaling and OL development via a S704/T7-5 phosphorylation mechanism, and determine a new role of the kinase CK2α in contributing to OL development. In-depth understanding of CK2α-Daam2 pathway regulation will allow us to precisely modulate its activity in conjunction with Wnt signaling and harness its biology for white matter pathology.
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。Wnt信号通路由多个调节层组成；因此，这些过程如何协调以调控少突胶质细胞的发育仍不清楚。在这里，我们表明CK2α，一种Wnt/β-连环蛋白信号的丝氨酸/苏氨酸激酶，在少突胶质细胞发育过程中磷酸化Daam2，抑制其功能和Wnt活性。有趣的是，我们发现Daam2磷酸化对少突胶质细胞发育的不同阶段有不同影响，加速早期分化，随后减缓成熟和髓鞘形成。应用于白质损伤研究发现，CK2α介导的Daam2磷酸化对新生儿缺氧后的发育和行为恢复起保护作用，同时促进成年脱髓鞘后的髓鞘修复。总之，我们的研究结果确定了Wnt通路中的一个新的调节节点，该节点通过蛋白质磷酸化诱导的信号复合物不稳定性来调节少突胶质细胞的发育，并突出了髓鞘修复的一种新的生物学机制。
Wnt信号通路在少突胶质细胞发育中起着至关重要的作用，并且被认为是白质损伤后髓鞘修复的不良事件。新兴研究揭示了Wnt效应器在少突胶质细胞谱系中的多模态作用，但少突胶质细胞髓鞘再生的潜在分子机制和可修饰靶点仍不清楚。利用基因小鼠发育和损伤模型系统，我们通过S704/T7-5磷酸化机制描绘了Daam2在Wnt信号通路和少突胶质细胞发育中的一个新的阶段特异性功能，并确定了激酶CK2α在促进少突胶质细胞发育中的新作用。深入了解CK2α-Daam²通路调节将使我们能够结合Wnt信号精确调节其活性，并利用其生物学特性来解决白质病理学问题。
