Department of Microbiology and Pediatric Research, Centre for Molecular Biology and Neurosciences, University of Oslo and Oslo University Hospital, Rikshospitalet, Nydalen, N-0424 Oslo, Norway.
Proc Natl Acad Sci U S A. 2011 Nov 15;108(46):18802-7. doi: 10.1073/pnas.1106880108. Epub 2011 Nov 7.
Neural stem/progenitor cell proliferation and differentiation are required to replace damaged neurons and regain brain function after hypoxic-ischemic events. DNA base lesions accumulating during hypoxic-ischemic stress are removed by DNA glycosylases in the base-excision repair pathway to prevent cytotoxicity and mutagenesis. Expression of the DNA glycosylase endonuclease VIII-like 3 (Neil3) is confined to regenerative subregions in the embryonic and perinatal brains. Here we show profound neuropathology in Neil3-knockout mice characterized by a reduced number of microglia and loss of proliferating neuronal progenitors in the striatum after hypoxia-ischemia. In vitro expansion of Neil3-deficient neural stem/progenitor cells revealed an inability to augment neurogenesis and a reduced capacity to repair for oxidative base lesions in single-stranded DNA. We propose that Neil3 exercises a highly specialized function through accurate molecular repair of DNA in rapidly proliferating cells.
神经干细胞/祖细胞的增殖和分化对于在缺氧缺血事件后替代受损神经元并恢复脑功能是必需的。在缺氧缺血应激过程中积累的 DNA 碱基损伤由碱基切除修复途径中的 DNA 糖苷酶去除，以防止细胞毒性和突变。DNA 糖苷酶内切酶 VIII 样 3 (Neil3) 的表达局限于胚胎和围产期大脑的再生亚区。在这里，我们展示了 Neil3 敲除小鼠的严重神经病理学特征，表现为缺氧缺血后纹状体中小胶质细胞数量减少和增殖性神经元祖细胞丢失。体外扩增 Neil3 缺陷的神经干细胞/祖细胞显示出无法增强神经发生的能力，以及修复单链 DNA 中氧化碱基损伤的能力降低。我们提出，Neil3 通过在快速增殖细胞中准确的分子修复来发挥高度专业化的功能。
