Retroviral lineage analysis of fibroblast growth factor receptor signaling in FGF2 inhibition of oligodendrocyte progenitor differentiation.
Fibroblast growth factor 2 (FGF2) inhibits oligodendrocyte progenitor cell (OPC) differentiation during development and limits remyelination following chronic demyelination. The current study examines the mechanism underlying this effect of FGF2 expression on OPC differentiation. Retroviral lineage tracing demonstrates a direct in vivo effect of FGF receptor (FGFR) signaling on OPC differentiation. Retrovirus expressing a dominant negative FGFR construct (FGFRdn) and green fluorescent protein (GFP) was injected into the dorsal columns of postnatal day 7 (P7) mice followed by perfusion at P28. Among the GFP-labeled cells, FGFRdn retrovirus generated a higher proportion of oligodendrocytes than did control infections. This result from FGFRdn expression in OPCs was similar to the result obtained in our previous study using control retrovirus in FGF2 null mice. Further, in vitro retroviral siRNA expression distinguishes the function of specific FGFR isoforms in OPC responses to FGF2. FGF2 inhibition of OPC differentiation was effectively blocked by siRNA targeted to FGFR1, but not FGFR2 or FGFR3. We propose a model of direct FGF2 activation of FGFR1 leading to inhibition of OPC differentiation. This signaling pathway may be an important regulator of oligodendrocyte generation during myelination in development and may perturb OPC generation of remyelinating oligodendrocytes in demyelinating disease.
Zhou
Yong-Xing
YX
Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814-4799, USA.
Flint
Nicole C
NC
Murtie
Joshua C
JC
Le
Tuan Q
TQ
Armstrong
Regina C
RC
D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D019070:Cell Lineage / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000494:pharmacology*; D005822:Genetic Vectors / Q000235:genetics; D049452:Green Fluorescent Proteins; D006131:Growth Inhibitors / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000378:metabolism; D009416:Nerve Regeneration / Q000502:physiology; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000187:drug effects / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism*; D014162:Transfection / Q000379:methods
D006131:Growth Inhibitors; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D016222:Fibroblast Growth Factor 2; D049452:Green Fluorescent Proteins; C496350:Fgfr1 protein, rat; D051496:Receptor, Fibroblast Growth Factor, Type 1