Abstract
Organisms and their cells vary greatly in their tolerance of low oxygen environments (hypoxia). A delineation of the determinants of hypoxia tolerance is incomplete, despite intense interest for its implications in diseases such as stroke and myocardial infarction. The insulin/IGF-1 receptor (IGFR) signaling pathway controls survival of Caenorhabditis elegans from a variety of stressors including aging, hyperthermia, and hypoxia. daf-2 encodes a C. elegans IGFR homolog whose primary signaling pathway modulates the activity of the FOXO transcription factor DAF-16. DAF-16 regulates the transcription of a large number of genes, some of which have been shown to control aging. To identify genes that selectively regulate hypoxic sensitivity, we compared the whole-organismal transcriptomes of three daf-2 reduction-of-function alleles, all of which are hypoxia resistant, thermotolerant, and long lived, but differ in their rank of severities for these phenotypes. The transcript levels of 172 genes were increased in the most hypoxia resistant daf-2 allele, e1370, relative to the other alleles whereas transcripts from only 10 genes were decreased in abundance. RNAi knockdown of 6 of the 10 genes produced a significant increase in organismal survival after hypoxic exposure as would be expected if down regulation of these genes by the e1370 mutation was responsible for hypoxia resistance. However, RNAi knockdown of these genes did not prolong lifespan. These genes definitively separate the mechanisms of hypoxic sensitivity and lifespan and identify biological strategies to survive hypoxic injury.
Highlights
Low ambient oxygen concentrations can induce cell death
We have previously shown that reduction-of-function mutations in the daf-2 gene confer powerful protection from hypoxic injury in the nematode Caenorhabditis elegans [1]. daf-2 encodes an insulin/ IGF-receptor homolog that signals through a conserved PI-3 kinase signaling cascade to regulate negatively the activity of a FOXO transcription factor, DAF-16 [2,3]. daf-2 reduction-offunction mutants are hypoxia resistant but are thermotolerant, long lived, and have a propensity to form dauer larvae, which are capable of long periods of hibernation in response to environmental stress [4]
Because of the very interesting biological processes controlled by the daf-2 – daf-16 pathway, considerable effort has been made to identify the downstream targets of the pathway [5,6,7,8,9,10,11,12]
Summary
Cells vary greatly in the level and duration of hypoxia that is required to produce their death. Identification of the determinants of hypoxic sensitivity has both biological and medical significance. We have previously shown that reduction-of-function mutations in the daf-2 gene confer powerful protection from hypoxic injury in the nematode Caenorhabditis elegans [1]. Because of the very interesting biological processes controlled by the daf-2 – daf-16 pathway, considerable effort has been made to identify the downstream targets of the pathway [5,6,7,8,9,10,11,12]. DAF-16 appears directly or indirectly to control the expression of a large number of diverse genes that often influence only a specific daf-2 phenotype
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