NG2 Regulates Directional Migration of Oligodendrocyte Precursor Cells via Rho GTPases and Polarity Complex Proteins
NG2 Regulates Directional Migration of Oligodendrocyte Precursor Cells via Rho GTPases and Polarity Complex Proteins
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DOI：
10.1523/jneurosci.5010-12.2013
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发表时间：
2013-06-26
影响因子：
5.3
通讯作者：
Trotter, Jacqueline
中科院分区：
文献类型：
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作者：
Biname, Fabien;Sakry, Dominik;Trotter, Jacqueline
跨膜蛋白多糖NG2由少突胶质前体细胞(OPC)表达，OPC在发育中的髓鞘形成过程中迁移到轴突，成年后迁移到损伤部位后重新髓鞘形成。高侵袭性神经胶质瘤也表达NG2。尽管NG2已经牵涉到控制OPC的迁移，但其行动模式仍然不为人知。在此，我们在体外和体内证明了NG2通过调节细胞的极性来控制OPC的迁移。在成年小鼠的刺伤中，我们发现NG2控制OPC朝向伤口的方向。NG2通过MUPP1/Syx1信号通路刺激细胞外周的RhoA活性，有利于OPC迁移的两极形状，从而定向迁移。当Thr-2256被磷酸化时，NG2的下游信号从RhoA转换到Rac刺激。这通过前后极性的调节器触发了生长过程，我们使用NG2的磷酸模拟形式证明了NG2确实招募了CRB和PAR极性复合体的蛋白质，通过全球环境基金Tiam1刺激RAC活性。我们的发现表明，NG2是Rho GTP酶活性和细胞内定位的核心组织者，控制着OPC的极性和定向迁移。这项工作还揭示了CRB和PAR极性复合体作为NG2信号的新效应器在建立前后极性中的作用。
The transmembrane proteoglycan NG2 is expressed by oligodendrocyte precursor cells (OPC), which migrate to axons during developmental myelination and remyelinate in the adult after migration to injured sites. Highly invasive glial tumors also express NG2. Despite the fact that NG2 has been implicated in control of OPC migration, its mode of action remains unknown. Here, we show in vitro and in vivo that NG2 controls migration of OPC through the regulation of cell polarity. In stab wounds in adult mice we show that NG2 controls orientation of OPC toward the wound. NG2 stimulates RhoA activity at the cell periphery via the MUPP1/Syx1 signaling pathway, which favors the bipolar shape of migrating OPC and thus directional migration. Upon phosphorylation of Thr-2256, downstream signaling of NG2 switches from RhoA to Rac stimulation. This triggers process outgrowth through regulators of front-rear polarity and we show using a phospho-mimetic form of NG2 that indeed NG2 recruits proteins of the CRB and the PAR polarity complexes to stimulate Rac activity via the GEF Tiam1. Our findings demonstrate that NG2 is a core organizer of Rho GTPase activity and localization in the cell, which controls OPC polarity and directional migration. This work also reveals CRB and PAR polarity complexes as new effectors of NG2 signaling in the establishment of front-rear polarity.