Although NG2 is known to be selectively expressed in oligodendrocyte precursor cells (OPCs) for many years, its expressional regulation and functional involvement in oligodendrocyte differentiation have remained elusive. Here, we report that the surface-bound NG2 proteoglycan can physically bind to PDGF-AA and enhances PDGF receptor alpha (PDGFRα) activation of downstream signaling. During differentiation stage, NG2 protein is cleaved by A disintegrin and metalloproteinase with thrombospondin motifs type 4 (Adamts4), which is highly upregulated in differentiating OPCs but gradually downregulated in mature myelinating oligodendrocytes. Genetic ablation of Adamts4 gene impedes NG2 proteolysis, leading to elevated PDGFRα signaling but impaired oligodendrocyte differentiation and axonal myelination in both sexes of mice. Moreover, Adamts4 deficiency also lessens myelin repair in adult brain tissue following Lysophosphatidylcholine-induced demyelination. Thus, Adamts4 could be a potential therapeutic target for enhancing oligodendrocyte differentiation and axonal remyelination in demyelinating diseases.

SIGNIFICANCE STATEMENT NG2 is selectively expressed in OPCs and downregulated during differentiation stage. To date, the molecular mechanism underlying the progressive removal of NG2 surface proteoglycan in differentiating OPCs has been unknown. In this study, we demonstrate that ADAMTS4 released by differentiating OPCs cleaves surface NG2 proteoglycan, attenuates PDGFRα signaling, and accelerates oligodendrocyte differentiation. In addition, our study also suggests ADAMTS4 as a potential therapeutic target for promoting myelin recovery in demyelinating diseases.

尽管多年来已知 NG2 在少突胶质细胞前体细胞 (OPC) 中选择性表达，但其在少突胶质细胞分化中的表达调控和功能参与仍然难以捉摸。在这里，我们报告表面结合的 NG2 蛋白多糖可以物理结合 PDGF-AA，并增强下游信号传导的 PDGF 受体 α ( PDGFR α) 激活。在分化阶段，NG2 蛋白被解整合素和具有 4 型血小板反应蛋白基序 ( Adamts4 ) 的金属蛋白酶裂解，该蛋白在分化 OPC 中高度上调，但在成熟髓鞘少突胶质细胞中逐渐下调。 Adamts4基因的遗传消除会阻碍 NG2 蛋白水解，导致 PDGFRα 信号传导升高，但会损害两性小鼠的少突胶质细胞分化和轴突髓鞘形成。此外， Adamts4缺陷还会减少成人脑组织在溶血磷脂酰胆碱诱导的脱髓鞘后的髓磷脂修复。因此， Adamts4可能是增强脱髓鞘疾病中少突胶质细胞分化和轴突髓鞘再生的潜在治疗靶点。

意义说明NG2 在 OPC 中选择性表达，并在分化阶段下调。迄今为止，在分化 OPC 过程中逐步去除 NG2 表面蛋白多糖的分子机制尚不清楚。在这项研究中，我们证明分化 OPC 释放的 ADAMTS4 会裂解表面 NG2 蛋白聚糖，减弱 PDGFRα 信号传导，并加速少突胶质细胞分化。此外，我们的研究还表明 ADAMTS4 作为促进脱髓鞘疾病中髓磷脂恢复的潜在治疗靶点。