Directed migration of oligodendroglial progenitor cells: role of NG2 and fyn kinase
Final Report Abstract
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 tumours also express NG2. In spite of the fact that NG2 has been implicated in control of OPC migration, its mode of action remains unknown. 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 towards the wound. NG2 stimulates RhoA activity at the cell periphery via the MUPP1/Syx1 signalling pathway which favours the bipolar shape of migrating OPC and thus directional migration. Upon phosphorylation of Thr-2256, downstream signalling 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 localisation in the cell which controls OPC polarity and directional migration. This work also reveals CRB and PAR polarity complexes as new effectors of NG2 signalling in the establishment of front-rear polarity.
