A distinct response to endogenous DNA damage in the development of Nbsl-deficient cortical neurons  

作　　者：Rui Li Yun-Gui Yang Yunzhou Gao Zhao-Qi Wang Wei-Min Tong 

机构地区：[1]Department of Pathology and Center for Experimental Animal Research,Institute of Basic Medical Sciences,Chinese Academy of Medical Sciences&Peking Union Medical College(PUMC),5 Dong Dan San Tiao,Beijing 100005,China [2]Genome Structure&Stability Group,Disease Genomics and Individualized Medicine Laboratory,Beijing Institute of Genomics,Chinese Academy of Sciences,Beijing 100029,China [3]Leibniz Institute for Age Research-Fritz Lipmann Institute [4]Faculty of Biology-Pharmacy,Friedrich-Schiller-University Jena,07745 Jena,Germany

出　　处：《Cell Research》2012年第5期859-872,共14页细胞研究（英文版）

摘　　要：Microcephaly is a clinical characteristic for human nijmegen breakage syndrome （NBS, mutated in NBS1 gene）, a chromosomal instability syndrome. However, the underlying molecular pathogenesis remains elusive. In the pres- ent study, we demonstrate that neuronal disruption of NBS （Nbn in mice） causes microcephaly characterized by the reduction of cerebral cortex and corpus callosum, recapitulating neuronal anomalies in human NBS. Nbsl-deficient neocortex shows accumulative endogenous DNA damage and defective activation of Ataxia telangiectasia and Rad3- related （ATR）-Chkl pathway upon DNA damage. Notably, in contrast to massive apoptotic cell death in Nbsl- deficient cerebella, activation of p53 leads to a defective neuroprogenitor proliferation in neocortex, likely via specific persistent induction of hematopoietic zinc finger （Hzf） that preferentially promotes p53-mediated cell cycle arrest whilst inhibiting apoptosis. Moreover, Trp53 mutations substantially rescue the microcephaly in Nbsl-deficient mice. Thus, the present results reveal the first clue that developing neurons at different regions of brain selectively respond to endogenous DNA damage, and underscore an important role for Nbsl in neurogenesis.

关 键 词：DNA damage response Nbsl MICROCEPHALY p53 Hzf 

分 类 号：Q523[生物学—生物化学] Q424