Abstract
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.
Graphical Abstract
The distinct signaling regulatory roles in the cortical atrophy and the cerebellar apoptosis of the newborn Nbn-deficient mice.
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Acknowledgments
This work was initiated in the International Agency for Research on Cancer (IARC), Lyon, France. We thank D Galendo, L Frappart and N Lyndrate (IARC) for the maintenance of the animal colonies. We thank Wei-Min Tong (IBMS/PUMC) for providing tissues and antibodies. This work was supported in part by IBMS/PUMC Director’s Fund (2007RC03), by National Natural Sciences Foundation of China (30970602), by National Novel Drug Development Fund (2009ZX09303-008) and by 111 Project (B08007).
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We declare that we have no conflict of interest.
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Liu, B., Chen, X. The Distinct Signaling Regulatory Roles in the Cortical Atrophy and Cerebellar Apoptosis of Newborn Nbn-Deficient Mice. Cell Mol Neurobiol 33, 1043–1053 (2013). https://doi.org/10.1007/s10571-013-9971-2
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DOI: https://doi.org/10.1007/s10571-013-9971-2