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

Abstract

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.

Stem Cell Glycolipids

“…Phosphatidylglucoside is a phosphoglycerolipid containing glucose linked to phosphatidic acid, which is found originally in human umbilical cord erythrocytes [79] and subsequently in HL60 human promyelocytic leukemia cells [80]. During development, this glycolipid exhibited the stage-and cell type-specific localization patterns; the expression level was especially high in radial glia and astrocytes in developing mouse brains [81]. Interestingly, treatment of mouse embryonic neural stem cells with antiphosphatidylglucoside antibody induced expression of an astrocyte marker gene, glial fibrillary acidic protein.…”

“…Interestingly, treatment of mouse embryonic neural stem cells with antiphosphatidylglucoside antibody induced expression of an astrocyte marker gene, glial fibrillary acidic protein. It has been suggested that the modulated localization of epidermal growth factor receptor in phosphatidylglucoside-rich cell surface microdomains and the activation of downstream signaling pathways are involved in this effect [81]. Phosphatidylglucoside may be involved in astrocyte differentiation of neural stem cells.…”

New insights on glucosylated lipids: Metabolism and functions

“…To this end, we used DIM21 antibody as an artificial ligand and found that adding DIM21 to cultured neural progenitor cells prepared from fetal mouse telencephalon results in the recruitment of EGF receptors into PtdGlc-rich lipid rafts, leading to the activation of EGF receptors [141]. In human neutrophils, DIM21 treatment induced Fas clustering, leading to Fas-dependent apoptotic cell death [138].…”

Glycerophospholipid regulation of modality-specific sensory axon guidance in the spinal cord

“…Phosphatidyl-b-D-glucoside {PtdGlc [2-O-arachidoyl-1-O-(1-stearoyl)-sn-glycer-3-yl]-b-D-glucopyranosyl phosphate; fig. S1A} is a membrane glycerophospholipid (3) that is localized to radial glia and nascent astrocytes (4,5). We showed that PtdGlc and its hydrolytic derivative lyso-phosphatidyl-b-D-glucoside (LysoPtdGlc; fig.…”