title: Requirement for DNA ligase IV during embryonic neuronal development.
abstract: 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.
authors: Development and Stem Cell Institute, Key Laboratory of Ministry of Education, Department of Paediatrics, West China Second University Hospital, Sichuan University, Chengdu, China.
authors: Susanne A
authors: SA
authors: Gatz
authors: Limei
authors: L
authors: Ju
authors: Ralph
authors: R
authors: Gruber
authors: Eva
authors: E
authors: Hoffmann
authors: Antony M
authors: AM
authors: Carr
authors: Zhao-Qi
authors: ZQ
authors: Wang
authors: Cong
authors: C
authors: Liu
authors: Penny A
authors: PA
authors: Jeggo
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics / Q000502:physiology / Q000528:radiation effects; D064007:Ataxia Telangiectasia Mutated Proteins; D001973:Bromodeoxyuridine / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins; D049109:Cell Proliferation / Q000528:radiation effects; D002552:Cerebral Ventricles / Q000166:cytology* / Q000196:embryology* / Q000528:radiation effects; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D003545:Cysteine / Q000235:genetics; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism; D004622:Embryo, Mammalian; D047108:Embryonic Development / Q000235:genetics / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000528:radiation effects; D006657:Histones / Q000378:metabolism; D020287:In Situ Nick-End Labeling / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D058953:Neural Stem Cells / Q000502:physiology / Q000528:radiation effects; D009474:Neurons / Q000502:physiology* / Q000528:radiation effects; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency; D011839:Radiation, Ionizing; D020825:T-Box Domain Proteins / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000172:deficiency; D000071857:Tumor Suppressor p53-Binding Protein 1; D014443:Tyrosine / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; C491198:Eomes protein, mouse; D006657:Histones; D020825:T-Box Domain Proteins; C498302:Trp53bp1 protein, mouse; D014404:Tubulin; D025521:Tumor Suppressor Proteins; D000071857:Tumor Suppressor p53-Binding Protein 1; C462941:beta3 tubulin, mouse; D014443:Tyrosine; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D011088:DNA Ligases; D000072481:DNA Ligase ATP; D001973:Bromodeoxyuridine; D003545:Cysteine