Abstract
BackgroundThe development of complex responses to hypoxia has played a key role in the evolution of mammals, as inadequate response to this condition is frequently associated with cardiovascular diseases, developmental disorders, and cancers. Though numerous studies have used mice and rats in order to explore mechanisms that contribute to hypoxia tolerance, these studies are limited due to the high sensitivity of most rodents to severe hypoxia. The blind subterranean mole rat Spalax is a hypoxia tolerant rodent, which exhibits unique longevity and therefore has invaluable potential in hypoxia and cancer research.ResultsUsing microarrays, transcript abundance was measured in brain and muscle tissues from Spalax and rat individuals exposed to acute and chronic hypoxia for varying durations. We found that Spalax global gene expression response to hypoxia differs from that of rat and is characterized by the activation of functional groups of genes that have not been strongly associated with the response to hypoxia in hypoxia sensitive mammals. Using functional enrichment analysis of Spalax hypoxia induced genes we found highly significant overrepresentation of groups of genes involved in anti apoptosis, cancer, embryonic/sexual development, epidermal growth factor receptor binding, coordinated suppression and activation of distinct groups of transcription factors and membrane receptors, in addition to angiogenic related processes. We also detected hypoxia induced increases of different critical Spalax hub gene transcripts, including antiangiogenic genes associated with cancer tolerance in Down syndrome human individuals.ConclusionsThis is the most comprehensive study of Spalax large scale gene expression response to hypoxia to date, and the first to use custom Spalax microarrays. Our work presents novel patterns that may underlie mechanisms with critical importance to the evolution of hypoxia tolerance, with special relevance to medical research.
Highlights
The development of complex responses to hypoxia has played a key role in the evolution of mammals, as inadequate response to this condition is frequently associated with cardiovascular diseases, developmental disorders, and cancers
Estimating the scale of hypoxia induced differential expression in Spalax Based on multiple probe sequences designed from the Spalax brain/muscle transcriptome assembly we created a custom Spalax microarray using Agilent earray technology
Experiment 2 (6% O2 6 hrs) aimed at detecting responses similar to those elicited under acute environmental hypoxia as measured in Spalax underground habitats after rainfall
Summary
The development of complex responses to hypoxia has played a key role in the evolution of mammals, as inadequate response to this condition is frequently associated with cardiovascular diseases, developmental disorders, and cancers. The blind subterranean mole rat Spalax is a hypoxia tolerant rodent, which exhibits unique longevity and has invaluable potential in hypoxia and cancer research. The mole rat, Spalax ehrenbergi superspecies, is a wild subterranean rodent which lives in underground habitats, characterized by extreme hypoxic/hypercapnic conditions, and darkness [1]. Spalax was suggested to belong to the Muroidea superfamily, and is closely related to Murine species (e.g., mice, rats). A. Spalax-Murine common ancestor was suggested to live approximately 39 million years ago [2], during which Spalax acquired unique biological mechanisms to cope with environmental hypoxia, darkness, and other underground related stresses. Unlike various hibernating and diving mammals which experience short episodes of internal/environmental hypoxia, Spalax lives under chronic environmental hypoxia [3]. Spalax survives at 3% O2 for up to 14 hours, as compared to less than 4 hours for rats [4]
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