Nbn gene inactivation in the CNS of mouse inhibits the myelinating ability of the mature cortical oligodendrocytes.

Abstract

Nijmegen Breakage Syndrome (NBS) is a recessive genetic disorder characterized by immunodeficiency, elevated sensitivity to ionizing radiation, chromosomal instability, microcephaly, and high predisposition to malignancies. Since the underlying molecular mechanisms of the NBS microcephaly are still obscure, thus our group previously inactivated the Nbn gene in the central nervous system (CNS) of mice by nestin-Cre targeting gene system, and generated Nbn(CNS-del) mice. Interestingly, the newborn Nbn(CNS-del) mice exhibit obvious microcephaly, which is accompanied by severe ataxia and balance deficiency. In this study presented here, we report that Nbn-deficiency induces the enhanced apoptosis of the mature oligodendrocytes at postnatal day 7, which further affects the myelination of the nerve fibers of cerebrum and corpus callosum.The distinct regulatory roles of Ataxia telangiectasia mutated (ATM) signaling and protein kinase B(Akt)/the mammalian target of Rapamycin (AKT/mTOR) signaling are responsible for the enhanced apoptosis of the Nbn-deficient oligodendrocytes. In addition, a series of transcriptional factors including histonedeacetylase (HDAC), zinc finger protein 191 (ZFP-191) and myelin sheath regulatory factor (MRF) play distinct roles in regulating the myelination of the Nbn-deficient oligodendrocytes. Based on these results, it concludes that ATM-Chk2-P53-P21 signaling pathway and the AKT/mTOR signaling pathway are both responsible for the enhanced apoptosis of the Nbn-deficient oligodendrocytes. HDAC, ZFP-191, and MRF are also involved in the pathogenesis of the hypomyelination of the Nbn-deficient oligodendrocytes.

• Authors: Bo Liu, Xin Chen, Zhao-Qi Wang, Wei-Min Tong
• Journal: Glia (Glia) Vol. 62 Issue 1 Pg. 133-44 (Jan 2014) ISSN: 1098-1136 [Electronic] United States
• PMID: 24272708 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Wiley Periodicals, Inc.

Chemical References

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

Topics

• Animals
• Animals, Newborn
• Apoptosis (physiology)
• Cell Cycle Proteins (genetics, metabolism)
• Cells, Cultured
• Central Nervous System (metabolism)
• Cerebral Cortex (cytology)
• Corpus Callosum (metabolism)
• DNA-Binding Proteins
• Down-Regulation (genetics)
• Mice
• Mice, Transgenic
• Myelin Proteins (metabolism)
• Myelin Sheath (metabolism, ultrastructure)
• Nestin (genetics)
• Nuclear Proteins (genetics, metabolism)
• Oligodendroglia (metabolism, physiology, ultrastructure)
• Signal Transduction (genetics, physiology)