Fibroblast growth factor signaling in oligodendrocyte-lineage cells facilitates recovery of chronically demyelinated lesions but is redundant in acute lesions.
Remyelination is a potent regenerative process in demyelinating diseases, such as multiple sclerosis, the effective therapeutic promotion of which will fill an unmet clinical need. The development of proregenerative therapies requires the identification of key regulatory targets that are likely to be involved in the integration of multiple signaling mechanisms. Fibroblast growth factor (FGF) signaling system, which comprises multiple ligands and receptors, potentially provides one such target. Since the FGF/FGF receptor (FGFR) interactions are complex and regulate multiple diverse functions of oligodendrocyte lineage cells, it is difficult to predict their overall therapeutic potential in the regeneration of oligodendrocytes and myelin. Therefore, to assess the integrated effects of FGFR signaling on this process, we simultaneously inactivated both FGFR1 and FGFR2 in oligodendrocytes and their precursors using two Cre-driver mouse lines. Acute and chronic cuprizone-induced or lysolecithin-induced demyelination was established in Fgfr1/Fgfr2 double knockout mice (dKO). We found that in the acute cuprizone model, there was normal differentiation of oligodendrocytes and recovery of myelin in the corpus callosum of both control and dKO mice. Similarly, in the spinal cord, lysolecithin-induced demyelinated lesions regenerated similarly in the dKO and control mice. In contrast, in the chronic cuprizone model, fewer differentiated oligodendrocytes and less efficient myelin recovery were observed in the dKO compared to control mice. These data suggest that while cell-autonomous FGF signaling is redundant during recovery of acute demyelinated lesions, it facilitates regenerative processes in chronic demyelination. Thus, FGF-based therapies have potential value in stimulating oligodendrocyte and myelin regeneration in late-stage disease.
Department of Neuroscience, University of Connecticut Medical School, Farmington, Connecticut.
Miki
M
Furusho
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute and Department of Veterinary Medicine, University of Cambridge, United Kingdom.
Aude J
AJ
Roulois
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute and Department of Veterinary Medicine, University of Cambridge, United Kingdom.
Robin J M
RJ
Franklin
Department of Neuroscience, University of Connecticut Medical School, Farmington, Connecticut.
Rashmi
R
Bansal
D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D019070:Cell Lineage / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D002614:Chelating Agents / Q000633:toxicity; D003471:Cuprizone / Q000633:toxicity; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000502:physiology*; D008244:Lysophosphatidylcholines / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013116:Spinal Cord / Q000473:pathology
D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; D051792:Basic Helix-Loop-Helix Proteins; D002614:Chelating Agents; D003471:Cuprizone; D005346:Fibroblast Growth Factors; D008244:Lysophosphatidylcholines; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051497:Receptor, Fibroblast Growth Factor, Type 2; C494786:Olig1 protein, mouse; C496349:Fgfr1 protein, mouse; C496354:Fgfr2 protein, mouse; C571338:Cnp protein, mouse
myelin; oligodendrocyte; remyelination