title: Limited remyelination in Theiler's murine encephalomyelitis due to insufficient oligodendroglial differentiation of nerve/glial antigen 2 (NG2)-positive putative oligodendroglial progenitor cells.
abstract: OBJECTIVE
  Limited remyelination is a key feature of demyelinating Theiler's murine encephalomyelitis (TME). It is hypothesized that a dysregulation of differentiation of oligodendroglial progenitor cells (OPCs) represents the main cause of insufficient regeneration in this model of multiple sclerosis.
  
  
  METHODS
  TME virus (TMEV)-infected SJL/J mice were evaluated by footprint analysis, light and electron microscopy, immunohistology, confocal immunofluorescence and RT-qPCR at multiple time points ranging from 1 h to 196 days post infection (dpi).
  
  
  RESULTS
  Footprint analysis revealed a significantly decreased stride length at 147 and 196 dpi. Demyelination progressively increased from 14 towards 196 dpi. A mild amount of remyelination was detected at 147 and 196 dpi. Early onset axonal injury was detected from 14 dpi on. TMEV RNA was detectable throughout the observation period and markedly increased between 7 and 28 dpi. Intralesional nerve/glial antigen 2 (NG2)-positive OPCs were temporarily increased between 28 and 98 dpi. Similarly, a transient upregulation of NG2 and platelet-derived growth factor alpha-receptor mRNA was noticed. In contrast, intralesional 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase)-positive oligodendrocytes were decreased between 56 and 196 dpi. Although CNPase mRNA remained unchanged, myelin basic protein mRNA and especially its exon 2 containing splice variants were decreased. Glial fibrillary acidic protein (GFAP)-positive astrocytes and GFAP mRNA were increased in the late phase of TME. A mildly increased colocalization of both NG2/CNPase and NG2/GFAP was revealed at 196 dpi.
  
  
  CONCLUSIONS
  Summarized, the present results indicated a dysregulation of OPC maturation as the main cause for the delayed and limited remyelination in TME. A shift of OPC differentiation from oligodendroglial towards astrocytic differentiation is postulated.
authors.affiliation: Department of Pathology, University of Veterinary Medicine Hannover, Bünteweg, Hannover, Germany. reiner.ulrich@tiho-hannover.de
authors.forename: R
authors.initials: R
authors.lastname: Ulrich
authors.forename: F
authors.initials: F
authors.lastname: Seeliger
authors.forename: M
authors.initials: M
authors.lastname: Kreutzer
authors.forename: P-G
authors.initials: PG
authors.lastname: Germann
authors.forename: W
authors.initials: W
authors.lastname: Baumgärtner
mesh_terms: D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000941:Antigens / Q000235:genetics / Q000378:metabolism*; D018188:Cardiovirus Infections / Q000473:pathology / Q000503:physiopathology* / Q000821:virology; D002454:Cell Differentiation; D004679:Encephalomyelitis / Q000473:pathology / Q000503:physiopathology* / Q000821:virology; D005260:Female; D015870:Gene Expression; D005904:Glial Fibrillary Acidic Protein; D007150:Immunohistochemistry; D051379:Mice; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D009103:Multiple Sclerosis / Q000473:pathology / Q000503:physiopathology*; D004676:Myelin Basic Protein / Q000235:genetics / Q000378:metabolism; D009186:Myelin Sheath / Q000473:pathology / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000502:physiology; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000473:pathology / Q000503:physiopathology / Q000821:virology; D013234:Stem Cells / Q000166:cytology* / Q000502:physiology; D017945:Theilovirus / Q000302:isolation & purification; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases; D000941:Antigens; D005904:Glial Fibrillary Acidic Protein; D004676:Myelin Basic Protein; D009419:Nerve Tissue Proteins; D011509:Proteoglycans; D012333:RNA, Messenger; D020796:Receptor, Platelet-Derived Growth Factor alpha; D000099216:Chondroitin Sulfate Proteoglycan 4; C528900:glial fibrillary astrocytic protein, mouse