A functional role for EGFR signaling in myelination and remyelination.
Cellular strategies for oligodendrocyte regeneration and remyelination involve characterizing endogenous neural progenitors that are capable of generating oligodendrocytes during normal development and after demyelination, and identifying the molecular signals that enhance oligodendrogenesis from these progenitors. Using both gain- and loss-of-function approaches, we explored the role of epidermal growth factor receptor (EGFR) signaling in adult myelin repair and in oligodendrogenesis. We show that 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) promoter-driven overexpression of human EGFR (hEGFR) accelerated remyelination and functional recovery following focal demyelination of mouse corpus callosum. Lesion repopulation by Cspg4+ (also known as NG2) Ascl1+ (also known as Mash1) Olig2+ progenitors and functional remyelination were accelerated in CNP-hEGFR mice compared with wild-type mice. EGFR overexpression in subventricular zone (SVZ) and corpus callosum during early postnatal development also expanded this NG2+Mash1+Olig2+ progenitor population and promoted SVZ-to-lesion migration, enhancing oligodendrocyte generation and axonal myelination. Analysis of hypomorphic EGFR-mutant mice confirmed that EGFR signaling regulates oligodendrogenesis and remyelination by NG2+Mash1+Olig2+ progenitors. EGFR targeting holds promise for enhancing oligodendrocyte regeneration and myelin repair.
Aguirre
Adan
A
Center for Neuroscience Research, Children's National Medical Center, 111 Michigan Ave., NW, Washington, DC 20010-2970, USA.
Dupree
Jeff L
JL
Mangin
J M
JM
Gallo
Vittorio
V
D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; D053687:Adult Stem Cells / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000503:physiopathology*; D004195:Disease Models, Animal; D004815:Epidermal Growth Factor / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D008244:Lysophosphatidylcholines; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009186:Myelin Sheath / Q000502:physiology* / Q000648:ultrastructure; D009416:Nerve Regeneration / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009836:Oligodendroglia / Q000502:physiology* / Q000648:ultrastructure; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D008244:Lysophosphatidylcholines; D009419:Nerve Tissue Proteins; D049452:Green Fluorescent Proteins; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D010727:Phosphoric Diester Hydrolases; D063309:2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; C571337:CNP protein, human; C571338:Cnp protein, mouse; D001973:Bromodeoxyuridine