DNA damage and oxidative injury are associated with hypomyelination in the corpus callosum of newborn Nbn(CNS-del) mice

J Neurosci Res. 2014 Feb;92(2):254-66. doi: 10.1002/jnr.23313. Epub 2013 Nov 23.


Nijmegen breakage syndrome (NBS), caused by mutation of the Nbn gene, is a recessive genetic disorder characterized by immunodeficiency, elevated sensitivity to ionizing radiation, chromosomal instability, microcephaly, and high predisposition to malignancies. To explore the underlying molecular mechanisms of NBS microcephaly, Frappart et al. previously inactivated Nbn gene in the central nervous system (CNS) of mice by the nestin-Cre targeting gene system and generated Nbn(CNS-del) mice. Here we first report that Nbn gene inactivation induces the defective proliferation and enhanced apoptosis of the oligodendrocyte precursor cells (OPCs), contributing to the severe hypomyelination of the nerve fibers of the corpus callosum. Under conditions of DNA damage and oxidative stress, the distinct regulatory roles of ATM-Chk2 signaling and AKT/mTOR signaling are responsible for the defective proliferation and enhanced apoptosis of the Nbn-deficient OPCs. In addition, specific HDAC isoforms may play distinctive roles in regulating the myelination of the Nbn-deficient OPCs. However, brain-derived neurotrophic factor and nerve growth factor stimulation attenuates the oxidative stress and thereby increases the proliferation of the Nbn-deficient OPCs, which is accompanied by upregulation of the AKT/mTOR/P70S6K signaling pathway. Taken together, these findings demonstrate that DNA damage and oxidative stress resulting from Nbn gene inactivation are associated with hypomyelination of the nerve fibers of corpus callosum.

Keywords: Nbn gene; OPCs; apoptosis; hypomyelination; proliferation; signaling pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Blotting, Western
  • Cell Cycle Proteins / genetics
  • Cells, Cultured
  • Corpus Callosum / pathology*
  • Corpus Callosum / physiopathology
  • DNA Damage / physiology*
  • DNA-Binding Proteins
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Immunohistochemistry
  • Mice
  • Mice, Mutant Strains
  • Myelin Sheath / pathology*
  • Neural Stem Cells / metabolism
  • Neural Stem Cells / pathology
  • Neurogenesis / physiology
  • Nijmegen Breakage Syndrome / genetics
  • Nijmegen Breakage Syndrome / pathology*
  • Nijmegen Breakage Syndrome / physiopathology
  • Nuclear Proteins / genetics
  • Oligodendroglia / metabolism
  • Oligodendroglia / pathology
  • Oxidative Stress / physiology*
  • Real-Time Polymerase Chain Reaction


  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Nijmegen breakage syndrome 1 protein, mouse
  • Nuclear Proteins