title: Inhibition of oligodendrocyte precursor cell differentiation by myelin-associated proteins.
abstract: OBJECTIVE
  Promoting repair of central nervous system (CNS) white matter represents an important approach to easing the course of a number of tragic neurological diseases. For this purpose, strategies are currently being evaluated for transplanting cells capable of generating new oligodendrocytes into areas of demyelination and/or enhancing the potential of endogenous stem/precursor cells to give rise to new oligodendrocytes. Emerging evidence, however, indicates that increasing the presence of cells capable of forming new myelin sheaths is not sufficient to promote repair because of unknown inhibitors that accumulate in lesions as a consequence of myelin degeneration and impair the generation of new oligodendrocytes. The aim of the present study was to characterize the nature of the inhibitory molecules present in myelin.
  
  
  METHODS
  Differentiation of primary rat oligodendrocyte precursor cells (OPCs) in the presence of CNS and peripheral nervous system myelin was assessed by immunocytochemical methods. The authors further characterized the nature of the inhibitors by submitting myelin membrane preparations to biochemical precipitation and digestion. Finally, OPCs were grown on purified Nogo-A, oligodendrocyte myelin glycoprotein, and myelin-associated glycoprotein, the most prominent inhibitors of axon regeneration.
  
  
  RESULTS
  Myelin membrane preparations induced a differentiation block in OPCs that was associated with down-regulation of expression of the transcription factor Nkx2.2. The inhibitory activity in myelin was restricted to the CNS and was predominantly associated with white matter. Furthermore, the results demonstrate that myelin proteins that are distinct from the most prominent inhibitors of axon outgrowth are specific inhibitors of OPC differentiation.
  
  
  CONCLUSIONS
  The inhibitory effect of unknown myelin-associated proteins should be considered in future treatment strategies aimed at enhancing CNS repair.
authors.affiliation: Department of Pediatrics, Medical University of Vienna, Austria.
authors.forename: Yasir A
authors.initials: YA
authors.lastname: Syed
authors.forename: Alexandra S
authors.initials: AS
authors.lastname: Baer
authors.forename: Gert
authors.initials: G
authors.lastname: Lubec
authors.forename: Harald
authors.initials: H
authors.lastname: Hoeger
authors.forename: Georg
authors.initials: G
authors.lastname: Widhalm
authors.forename: Mark R
authors.initials: MR
authors.lastname: Kotter
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000378:metabolism; D016466:CHO Cells; D002454:Cell Differentiation; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D004676:Myelin Basic Protein / Q000378:metabolism* / Q000494:pharmacology; D009836:Oligodendroglia / Q000187:drug effects / Q000502:physiology*; D016548:Prosencephalon / Q000166:cytology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection / Q000379:methods; D029961:Zebrafish Proteins
chemical_list: D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D004676:Myelin Basic Protein; C000715628:Nkx2-2 protein, rat; D014157:Transcription Factors; D029961:Zebrafish Proteins; C000715630:nkx2.2b protein, zebrafish