FGF plays a subtle role in oligodendrocyte maintenance in vivo.
Numerous in vitro studies indicate that fibroblast growth factors (FGFs) play a role in both the development and maintenance of oligodendrocytes. Addition of FGF to mature oligodendrocytes in culture was reported to downregulate the expression of genes encoding proteins of the myelin sheath and to induce a loss of myelin compaction. In this study, a model was developed to functionally block FGF signaling in oligodendrocytes in vivo, by generating transgenic mice expressing a dominant-negative FGF receptor (FGFR1), under the control of the myelin basic protein (MBP) promoter. To demonstrate the effectiveness of this model, truncated FGFR1 was first overexpressed in an FGF-responsive cell line in vitro. It was confirmed that FGF-signalling was blocked in these cells. Subsequently, five independent transgenic lines ("MBP-FRD") were generated. Three lines expressing the highest level of the transgene were further studied. Initial investigation by Western blot and light microscopic analyses revealed no apparent alterations in myelination of the MBP-FRD mouse brains. However, ultrastructural analysis of myelinated optic nerve fibres from two independent MBP-FRD lines revealed a significant increase in myelin thickness as a function of fibre diameter for both transgenic lines (13% and 16% increase). This increase in myelin thickness was not accompanied by alterations in myelin compaction. These results support the idea that FGF signaling in oligodendrocytes plays a role in the modulation of axon myelination in vivo.
Harari
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The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Finkelstein
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Bernard
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D000818:Animals; D015153:Blotting, Western; D001923:Brain Chemistry; D002478:Cells, Cultured; D005260:Female; D016220:Fibroblast Growth Factor 1 / Q000494:pharmacology*; D015870:Gene Expression / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D016296:Mutagenesis; D009185:Myelin Proteins / Q000032:analysis; D009186:Myelin Sheath / Q000737:chemistry / Q000648:ultrastructure; D009460:Neurologic Examination; D009836:Oligodendroglia / Q000166:cytology* / Q000187:drug effects* / Q000648:ultrastructure; D009900:Optic Nerve / Q000166:cytology; D011401:Promoter Regions, Genetic / Q000502:physiology; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D017468:Receptors, Fibroblast Growth Factor / Q000737:chemistry / Q000235:genetics*; D019076:Transgenes / Q000502:physiology
D009185:Myelin Proteins; D017468:Receptors, Fibroblast Growth Factor; D016220:Fibroblast Growth Factor 1; D011505:Protein-Tyrosine Kinases