Genome-wide analysis of gene expression in postnatal hippocampus of Neil1 and Neil2-deficient mice after hypoxia ischemia (HI)
NEIL 1-3 DNA glycosylases initiate the base excision repair pathway by removing oxidized bases from the DNA. NEIL1 and NEIL3 have been shown to protect the brain from ischemic stroke-induced injury in adult and perinatal mice, respectively. To assess the role of NEIL1 and NEIL2 in newborn mice, we used the Levine model of hypoxic-ischemic encephalopathy (HIE), modified for use in perinatal mice. We found that NEIL1 deficiency increased sensitivity to cerebral ischemia in newborn mice. In contrast, NEIL2 deficiency rendered the mice more resistant to hypoxia-ischemia. Importantly, no effect was seen in mice expressing base excision activity-deficient NEIL proteins and the global levels of the oxidative DNA lesion 5-hydroxycytosine, which is a substrate for the NEIL enzymes, did not differ significantly between the genotypes. Transcriptome analysis of NEIL1- and NEIL2-deficient hippocampus revealed changes in Neil2-deficient hippocampus that favour cell survival and limit brain injury after HI.  Our data suggest a role of NEIL2 in regulating the early transcriptional stress response, critical for neuronal cell death, after brain injury. This function seems to be independent of the base excision activity of the proteins.  The protective effect of NEIL2 deficiency makes NEIL2 a potential therapeutic target in treatment of perinatal HIE. Overall design: Postnatal day 10 mice deficient for the DNA glycosylases Neil1 and Neil2 were subjected to HI for 3h and 6h, respectively. The hippocampus from the contralateral- and ipsilateral side was collected from two replicates of each genotype and time point and RNA isolated for transcriptome profiling.