Central Nervous System Nbn Gene Knockout Mouse Cerebral Cortex Glial Cell Function Change

In response to DNA damage, Mrell/Rad50/Nbsl (MRN) complex acts as a DNA double-strand break sensor and functions in response to DNA damage through regulating damage pathway related proteins. Nijmegen breakage syndrome (NBS) is a genomic instability disease caused by hypomorphic mutations of NBS1gene encoding Nbsl protein. The clinical features of NBS syndrome consist of microcephaly,immunodeficiency,developmental deficiency,chromosomal instability and malignant predisposition.To further explore the pathogenesis of NBS microcephaly, we have generated a mouse model (termed as NbnCNS-del mice), by inactivating Nbn gene in the mouse central nervous system (CNS) with nestin-Cre targeting gene system. The phenotypes of this mouse model are similar to the symptoms of NBS patients, supporting our research on exploring the molecular mechanisms of NBS microcephaly. We have observed that the cerebral structure of early postnatal NbnCNS-del mice formed with severe neurodegeneration changes. However, the cerebella structure of early postnatal NbnCNS-del mice can hardly form with much more severe neurodegeneration changes. Besides, we also observed apparent myelination deficiency in early postnatal cerebral medulla and brain stem of NbnCXS-del mice, indicating that Nbsl would participate in myelination.In this study, we explored the glial neurotrophic protecting roles for neurons in early postnatal NbnCMS-del mice cerebral with the purpose to elucidate the molecular mechanisms of neurodegeneration and myelination deficiency. In current study, we reported that Nbsl deficiency in astrocytes of early postnatal NbnCNS-del mice cerebral contributed to the low secretion of nerve growth factor (NGF) and brain derived neurotrophic factor(BDNF). However, the secretion of neurotrophin-3(NT-3) was not affected. The low secretion of NGF did not affect the protein expression levels of tyrosine kinase A (TrkA) receptor and P75neurotrophic receptor (P75NTR). However, it reduced the interactions between TrkA and P75NTR respectively. The reduced secretion of NGF and BDNF from astrocyte further down-regulated the phosphorylation levels of mammallian rapamycin targeting protein (mTOR) and S6ribosomal protein (S6RP), contributing to reduced neurotrophic protecting roles for neuronal growth and nerve fiber myelination. The reduced Nbsl protein level in the microglias of NbnCNS del mice contributed to the low secretion of interleukin-1(IL-1) and interlukin-6(IL-6), contributing to the down-regulation of the phosphorylation levels of NF-k B and IκBα and reduction of inflammatory protecting roles for neuronal growth and myelination in cerebral. We also reported that the Nbsl deficiency in oligodendrocytes inhibited the protein expression levels of myelin sheath basic protein (MBP) and myelinating transcriptional factor oligol in early postnatal cerebral of NbnCNS del mice, contributing to myelination defects of CNS nerve fibers by down-regulating neurotrophic and inflammatory protecting roles.Taken together, these data indicated that the inactivation of Nbn gene in the mouse CNS inhibited the protein expression level of Nbsl, which reduced astrocytal and microglial neurotrophic protecting roles for neuronal growth and myelination through down-regulating mTOR/S6and NF-kB signaling pathways respectively, in early postnatal cerebral cortex.