Journal Article

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

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

2012

Overview

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.

• Subject: DNA损伤 / 内源性 / 反应 / 国家统计局 / 基因突变 / 大脑皮层 / 皮层神经元 / 细胞周期阻滞