Lipid rafts enriched in phosphatidylglucoside direct astroglial differentiation by regulating tyrosine kinase activity of epidermal growth factor receptors

Membrane lipid rafts provide a specialized microenvironment enriched with sphingolipids and phospholipids containing saturated fatty acids and serve as a platform for various intracellular signalling pathways. PtdGlc (phosphatidylglucoside) is a type of glycophospholipid localized in the outer leaflet of the plasma membrane. Owing to PtdGlc's unique fatty acid composition, exclusively composed of C_18:0 at sn-1 and C_20:0 at sn-2 of the glycerol backbone, it tends to form PGLRs (PtdGlc-enriched lipid rafts). Previously, we demonstrated that PGLRs reside on the cell surface of astroglial cells from fetal rat brain [Nagatsuka, Horibata, Yamazaki, Kinoshita, Shinoda, Hashikawa, Koshino, Nakamura and Hirabayashi (2006) Biochemistry 45, 8742-8750]. In the present study, we observed PGLRs in astroglial lineage cells at mid-embryonic to early-postnatal stages of developing mouse cortex. This suggests that PGLRs are developmentally correlated with astroglial differentiation during fetal cortical development. Our cell culture studies with multipotent neural progenitor cells prepared from fetal mouse telencephalon demonstrated that treatment with EGF (epidermal growth factor) or anti-PtdGlc antibody caused recruitment of EGFRs (EGF receptors) into lipid raft compartments, leading to activation of EGFRs. Moreover, the activation of EGFRs by antibody triggered downstream tyrosine kinase signalling and induced marked GFAP (glial fibrillary acidic protein) expression via the JAK (Janus kinase)/STAT (signal transducer and activator of transcription) signalling pathway. These findings strongly suggest that PGLRs are physiologically coupled to activated EGFRs on neural progenitor cells during fetal cortical development, and thereby play a distinct role in mediating astrogliogenesis.