Non-cell autonomous impairment of oligodendrocyte differentiation precedes CNS degeneration in the Zitter rat: implications of macrophage/microglial activation in the pathogenesis

BMC Neurosci. 2008 Apr 5:9:35. doi: 10.1186/1471-2202-9-35.

Abstract

Background: The zitter (zi/zi) rat, a loss-of-function mutant of the glycosylated transmembrane protein attractin (atrn), exhibits widespread age-dependent spongiform degeneration, hypomyelination, and abnormal metabolism of reactive oxygen species (ROS) in the brain. To date, the mechanisms underlying these phenotypes have remained unclear.

Results: Here, we show differentiation defects in zi/zi oligodendrocytes, accompanied by aberrant extension of cell-processes and hypomyelination. Axonal bundles were relatively preserved during postnatal development. With increasing in age, the injured oligodendrocytes in zi/zi rats become pathological, as evidenced by the accumulation of iron in their cell bodies. Immunohistochemical analysis revealed that atrn expression was absent from an oligodendrocyte lineage, including A2B5-positive progenitors and CNPase-positive differentiated cells. The number and distribution of Olig2-positive oligodendrocyte progenitors was unchanged in the zi/zi brain. Furthermore, an in vitro differentiation assay of cultured oligodendrocyte progenitors prepared from zi/zi brains revealed their normal competence for proliferation and differentiation into mature oligodendrocytes. Interestingly, we demonstrated the accelerated recruitment of ED1-positive macrophages/microglia to the developing zi/zi brain parenchyma prior to the onset of hypomyelination. Semiquantitative RT-PCR analysis revealed a significant up-regulation of CD26 and IL1-beta in the zi/zi brain during this early postnatal stage.

Conclusion: We demonstrated that the onset of the impairment of oligodendrocyte differentiation occurs in a non-cell autonomous manner in zi/zi rats. Hypomyelination of oligodendrocytes was not due to a failure of the intrinsic program of oligodendrocytes, but rather, was caused by extrinsic factors that interrupt oligodendrocyte development. It is likely that macrophage/microglial activation in the zi/zi CNS leads to disturbances in oligodendrocyte differentiation via deleterious extrinsic factors, such as the cytokine IL1-beta or ROS. Atrn might be involved in the activation of brain macrophages/microglia by suppressing excessive migration of monocytes into the CNS, or by accelerating the transformation of brain monocytes into resting microglia. Understanding the pathogenesis of the zi/zi rat may provide novel insights into the developmental interaction betweens macrophages/microglia and cells of an oligodendrocyte lineage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / cytology*
  • Brain / metabolism
  • Brain / pathology
  • Cell Differentiation / genetics*
  • Dipeptidyl Peptidase 4 / biosynthesis
  • Ferritins / metabolism
  • Immunohistochemistry
  • Interleukin-1beta / biosynthesis
  • Iron / metabolism
  • Macrophage Activation / physiology
  • Macrophages / metabolism
  • Membrane Proteins / genetics
  • Microglia / metabolism*
  • Mutation
  • Nerve Degeneration*
  • Oligodendroglia / cytology*
  • Oligodendroglia / pathology
  • Rats
  • Rats, Mutant Strains
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Atrn protein, rat
  • Interleukin-1beta
  • Membrane Proteins
  • Ferritins
  • Iron
  • Dipeptidyl Peptidase 4