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The zebrafish embryo as a dynamic model of anoxia tolerance.

ABSTRACT: Developing organisms depend upon a delicate balance in the supply and demand of energy to adapt to variable oxygen availability, although the essential mechanisms determining such adaptation remain elusive. In this study, we examine reversible anoxic arrest and dynamic bioenergetic transitions during zebrafish development. Our data reveal that the duration of anoxic viability corresponds to the developmental stage and anaerobic metabolic rate. Diverse chemical inhibitors of mitochondrial oxidative phosphorylation induce a similar arrest in normoxic embryos, suggesting a pathway responsive to perturbations in aerobic energy production rather than molecular oxygen. Consistent with this concept, arrest is accompanied by rapid activation of the energy-sensing AMP-activated protein kinase pathway, demonstrating a potential link between the sensing of energy status and adaptation to oxygen availability. These observations permit mechanistic insight into energy homeostasis during development that now enable genetic and small molecule screens in this vertebrate model of anoxia tolerance.

SUBMITTER: Mendelsohn BA

PROVIDER: S-EPMC3081722 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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The zebrafish embryo as a dynamic model of anoxia tolerance.

Mendelsohn Bryce A BA Kassebaum Bethany L BL Gitlin Jonathan D JD

Developmental dynamics : an official publication of the American Association of Anatomists 20080701 7

Developing organisms depend upon a delicate balance in the supply and demand of energy to adapt to variable oxygen availability, although the essential mechanisms determining such adaptation remain elusive. In this study, we examine reversible anoxic arrest and dynamic bioenergetic transitions during zebrafish development. Our data reveal that the duration of anoxic viability corresponds to the developmental stage and anaerobic metabolic rate. Diverse chemical inhibitors of mitochondrial oxidati ...[more]

PMID: 18521954

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Project description:Spermatozoa carry DNA damage that must be repaired by the oocyte machinery upon fertilization. Different strategies could be adopted by different vertebrates to face the paternal genotoxic damage. Mammals have strong sperm selection mechanisms and activate a zygotic DNA damage response (DDR) (including cell cycle arrest, DNA repair and alternative apoptosis) in order to guarantee the genomic conformity of the reduced progeny. However, external fertilizers, with different reproductive strategies, seem to proceed distinctively. Previous results from our group showed a downregulation of apoptotic activity in trout embryos with a defective DNA repairing ability, suggesting that mechanisms of tolerance to damaged DNA could be activated in fish to maintain cell survival and to progress with development. In this work, zebrafish embryos were obtained from control or UV-irradiated sperm (carrying more than 10% of fragmented DNA but still preserving fertilization ability). DNA repair (γH2AX and 53BP1 foci), apoptotic activity, expression of genes related to DDR and malformation rates were analyzed throughout development. Results showed in the progeny from damaged sperm, an enhanced repairing activity at the mid-blastula transition stage that returned to its basal level at later stages, rendering at hatching a very high rate of multimalformed larvae. The study of transcriptional and post-translational activity of tp53 (ZDF-GENE-990415-270) revealed the activation of an intense DDR in those progenies. However, the downstream pro-apoptotic factor noxa (ZDF-GENE-070119-3) showed a significant downregulation, whereas the anti-apoptotic gene bcl2 (ZDF-GENE-051015-1) was upregulated, triggering a repressive apoptotic scenario in spite of a clear genomic instability. This repression can be explained by the observed upregulation of p53 isoform Δ113p53, which is known to inhibit bcl2 transcription. Our results showed that tp53 is involved in DNA damage tolerance (DDT) pathways, allowing the embryo survival regardless of the paternal DNA damage. DDT could be an evolutionary mechanism in fish: tolerance to unrepaired sperm DNA could introduce new mutations, some of them potentially advantageous to face a changing environment.

Project description:Background: Extreme anoxia tolerance requires a metabolic depression whose modulation could involve small non-coding RNAs (small ncRNAs), which are specific, rapid, and reversible regulators of gene expression. A previous study of small ncRNA expression in embryos of the annual killifish Austrofundulus limnaeus, the most anoxia-tolerant vertebrate known, revealed a specific expression pattern of small ncRNAs that could play important roles in anoxia tolerance. Here, we conduct a comparative study on the presence and expression of small ncRNAs in the most anoxia-tolerant representatives of several major vertebrate lineages, to investigate the evolution of and mechanisms supporting extreme anoxia tolerance. The epaulette shark (Hemiscyllium ocellatum), crucian carp (Carassius carassius), western painted turtle (Chrysemys picta bellii), and leopard frog (Rana pipiens) were exposed to anoxia and recovery, and small ncRNAs were sequenced from the brain (one of the most anoxia-sensitive tissues) prior to, during, and following exposure to anoxia. Results: Small ncRNA profiles were broadly conserved among species under normoxic conditions, and these expression patterns were largely conserved during exposure to anoxia. In contrast, differentially expressed genes are mostly unique to each species, suggesting that each species may have evolved distinct small ncRNA expression patterns in response to anoxia. Mitochondria-derived small ncRNAs (mitosRNAs) which have a robust response to anoxia in A. limnaeus embryos, were identified in the other anoxia tolerant vertebrates here but did not display a similarly robust response to anoxia. Conclusion: These findings support an overall stabilization of the small ncRNA transcriptome during exposure to anoxic insults, but also suggest that multiple small ncRNA expression pathways may support anoxia tolerance, as no conserved small ncRNA response was identified among the anoxia-tolerant vertebrates studied. This may reflect divergent strategies to achieve the same endpoint: anoxia tolerance. However, it may also indicate that there are multiple cellular pathways that can trigger the same cellular and physiological survival processes, including hypometabolism.

Dataset Information

The zebrafish embryo as a dynamic model of anoxia tolerance.

Publications

The zebrafish embryo as a dynamic model of anoxia tolerance.

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