DNA-PK promotes the survival of young neurons in the embryonic mouse retina

被引:17
作者
Baleriola, J. [1 ]
Suarez, T. [1 ]
de la Rosa, E. J. [1 ]
机构
[1] CSIC, Ctr Invest Biol, Dept Cellular & Mol Med, Lab Dev Differentiat & Degenerat 3D, E-28040 Madrid, Spain
关键词
double-strand break; DNA repair; NHEJ; apoptosis; programmed cell death; neuronal differentiation; NERVOUS-SYSTEM DEVELOPMENT; PROGRAMMED CELL-DEATH; END-JOINING PROTEINS; DOUBLE-STRAND BREAKS; ATAXIA-TELANGIECTASIA; L1; RETROTRANSPOSITION; NEUROLOGICAL DISEASE; APOPTOSIS; MICE; REPAIR;
D O I
10.1038/cdd.2010.46
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Programmed cell death is a crucial process in neural development that affects mature neurons and glial cells, as well as proliferating precursors and recently born neurons at earlier stages. However, the regulation of the early phase of neural cell death and its function remain relatively poorly understood. In mouse models defective in homologous recombination or nonhomologous end-joining (NHEJ), which are both DNA double-strand break (DSB) repair pathways, there is massive cell death during neural development, even leading to embryonic lethality. These observations suggest that natural DSBs occur frequently in the developing nervous system. In this study, we have found that several components of DSB repair pathways are activated in the developing mouse retina at stages that coincide with the onset of neurogenesis. In short-term organotypic retinal cultures, we confirmed that the repair pathways can be modulated pharmacologically. Indeed, inhibiting the DNA-dependent protein kinase (DNA-PK) catalytic subunit, which is involved in NHEJ, with NU7026 increased caspase-dependent cell death and selectively reduced the neuron population. This observation concurs with an increase in the number of apoptotic neurons found after NU7026 treatment, as also observed in the embryonic scid mouse retina, a mutant that lacks DNA-PK catalytic subunit activity. Therefore, our results implicate the generation of DSB and DNA-PK-mediated repair in neurogenesis in the developing retina. Cell Death and Differentiation (2010) 17, 1697-1706; doi:10.1038/cdd.2010.46; published online 7 May 2010
引用
收藏
页码:1697 / 1706
页数:10
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