Abstract
BackgroundSince normal brain function depends upon continuous oxygen delivery and short periods of hypoxia can precondition the brain against subsequent ischemia, this study examined the effects of brief hypoxia on the whole genome transcriptional response in adult mouse brain.ResultPronounced changes of gene expression occurred after 3 hours of hypoxia (8% O2) and after 1 hour of re-oxygenation in all brain regions. The hypoxia-responsive genes were predominantly up-regulated in hindbrain and predominantly down-regulated in forebrain - possibly to support hindbrain survival functions at the expense of forebrain cognitive functions. The up-regulated genes had a significant role in cell survival and involved both shared and unshared signaling pathways among different brain regions. Up-regulation of transcriptional signaling including hypoxia inducible factor, insulin growth factor (IGF), the vitamin D3 receptor/retinoid X nuclear receptor, and glucocorticoid signaling was common to many brain regions. However, many of the hypoxia-regulated target genes were specific for one or a few brain regions. Cerebellum, for example, had 1241 transcripts regulated by hypoxia only in cerebellum but not in hippocampus; and, 642 (54%) had at least one hepatic nuclear receptor 4A (HNF4A) binding site and 381 had at least two HNF4A binding sites in their promoters. The data point to HNF4A as a major hypoxia-responsive transcription factor in cerebellum in addition to its known role in regulating erythropoietin transcription. The genes unique to hindbrain may play critical roles in survival during hypoxia.ConclusionDifferences of forebrain and hindbrain hypoxia-responsive genes may relate to suppression of forebrain cognitive functions and activation of hindbrain survival functions, which may coordinately mediate the neuroprotection afforded by hypoxia preconditioning.
Highlights
Since normal brain function depends upon continuous oxygen delivery and short periods of hypoxia can precondition the brain against subsequent ischemia, this study examined the effects of brief hypoxia on the whole genome transcriptional response in adult mouse brain
Many hypoxia regulated gene products are in the nucleus A one-way ANOVA, corrected for multiple comparisons using a False Discovery Rate of 5%, yielded 2,324 transcripts that changed 1.5 fold or more in at least one brain region after hypoxia preconditioning” (HP) treatment in adult C57BL/6 mice
The other 12 hypoxia inducible factor (HIF)-1a target genes were differentially regulated in different brain regions (Additional file 2 table S1)
Summary
Since normal brain function depends upon continuous oxygen delivery and short periods of hypoxia can precondition the brain against subsequent ischemia, this study examined the effects of brief hypoxia on the whole genome transcriptional response in adult mouse brain. It is known that certain brain regions and cells, such as hippocampal pyramidal neurons, striatal medium spiny neurons and cerebellar Purkinje neurons, are quite vulnerable to hypoxia/ischemia whereas others can be relatively resistant[13,14]. It is still not clear whether hypoxia/ HP responses could have predominantly engaged common or different mechanisms in different regions. Our current study further examined the regional response to HP systemically at the genomic level to determine whether there were common as well as region-specific responses to hypoxia (8% O2) in the brain
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