The distinct signaling regulatory roles in the cortical atrophy and cerebellar apoptosis of newborn Nbn-deficient mice.
Human Nijmegen breakage syndrome, caused by the hypomorphic mutation of Nbn gene, is a hereditary instability disease, characterized by chromosomal instability, immunodeficiency, radiosensitivity, cancer predisposition and microcephaly. To study the roles of Nbn protein in microcephaly, Nbn gene was specifically deleted in the central nervous system of mice by nestin-Cre targeting gene system (Frappart et al. in Nat Med 11:538-544, 2005). Strikingly, newborn Nbn-deficient mice exhibit the evident microcephalic cerebellum, which contributes to severe ataxia and balance deficiency. In this study, we first report that PI3K/AKT/mTOR signaling pathway that performs neurotrophic-protecting role in neuronal growth is significantly inhibited in newborn Nbn-deficient cortex and cerebellum. In addition, JNK signaling and ATR signaling are likely to converge to regulate the cerebellar apoptosis of newborn Nbn-deficient mice.
The Department of Pathology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, 5 DongDan SanTiao, Beijing, 100005, China, neurocomerpumc@hotmail.com.
Bo
B
Liu
Xin
X
Chen
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D001284:Atrophy; D018797:Cell Cycle Proteins / Q000172:deficiency* / Q000378:metabolism; D002531:Cerebellum / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D002540:Cerebral Cortex / Q000473:pathology*; D064447:Checkpoint Kinase 2 / Q000378:metabolism; D004268:DNA-Binding Proteins; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008831:Microcephaly / Q000378:metabolism / Q000473:pathology; D009186:Myelin Sheath / Q000473:pathology; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D009687:Nuclear Proteins / Q000172:deficiency* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D038601:Ribosomal Protein S6 / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D064447:Checkpoint Kinase 2; D004268:DNA-Binding Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D038601:Ribosomal Protein S6; D058570:TOR Serine-Threonine Kinases; C466108:Nijmegen breakage syndrome 1 protein, mouse; C576325:Atm protein, mouse; C578633:Chek2 protein, mouse