Requirement for DNA Ligase IV during Embryonic Neuronal Development

被引:57
作者
Gatz, Susanne A. [1 ,2 ]
Ju, Limei [1 ]
Gruber, Ralph [3 ]
Hoffmann, Eva [1 ]
Carr, Antony M. [1 ]
Wang, Zhao-Qi [3 ,4 ]
Liu, Cong [1 ,2 ]
Jeggo, Penny A. [1 ]
机构
[1] Univ Sussex, Genome Damage & Stabil Ctr, Brighton BN1 9RQ, E Sussex, England
[2] Sichuan Univ, Dev & Stem Cell Inst, Key Lab Minist Educ, Dept Paediat,W China Univ Hosp 2, Chengdu 610041, Peoples R China
[3] Fritz Lipmann Inst, Leibniz Inst Age Res, D-07745 Jena, Germany
[4] Univ Jena, Fac Biol Pharm, D-07745 Jena, Germany
基金
英国医学研究理事会;
关键词
DOUBLE-STRAND BREAKS; INTERMEDIATE PROGENITOR CELLS; NERVOUS-SYSTEM; ATAXIA-TELANGIECTASIA; HOMOLOGOUS RECOMBINATION; STEM-CELLS; ATM; REPAIR; DAMAGE; MICE;
D O I
10.1523/JNEUROSCI.1324-11.2011
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
The embryonic ventricular and subventricular zones (VZ/SVZ) contain the neuronal stem and progenitor cells and undergo rapid proliferation. The intermediate zone (IZ) contains nonreplicating, differentiated cells. The VZ/SVZ is hypersensitive to radiation-induced apoptosis. Ablation of DNA non-homologous end-joining (NHEJ) proteins, XRCC4 or DNA ligase IV (LigIV), confers ataxia telangiectasia mutated (ATM)-dependent apoptosis predominantly in the IZ. We examine the mechanistic basis underlying these distinct sensitivities using a viable LigIV (Lig4(Y288C)) mouse, which permits an examination of the DNA damage responses in the embryonic and adult brain. Via combined analysis of DNA breakage, apoptosis, and cell-cycle checkpoint control in tissues, we show that apoptosis in the VZ/SVZ and IZ is activated by low numbers of DNA double-strand breaks (DSBs). Unexpectedly, high sensitivity in the VZ/SVZ arises from sensitive activation of ATM-dependent apoptosis plus an ATM-independent process. In contrast, the IZ appears to be hypersensitive to persistent DSBs. NHEJ functions efficiently in both compartments. The VZ/SVZ and IZ regions incur high endogenous DNA breakage, which correlates with VZ proliferation. We demonstrate a functional G(2)/M checkpoint in VZ/SVZ cells and show that it is not activated by low numbers of DSBs, allowing damaged VZ/SVZ cells to transit into the IZ. We propose a novel model in which microcephaly in LIG4 syndrome arises from sensitive apoptotic induction from persisting DSBs in the IZ, which arise from high endogenous breakage in the VZ/SVZ and transit of damaged cells to the IZ. The VZ/SVZ, in contrast, is highly sensitive to acute radiation-induced DSB formation.
引用
收藏
页码:10088 / 10100
页数:13
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