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Mutation in pre-mRNA adenosine deaminase markedly attenuates neuronal tolerance to O2 deprivation in Drosophila melanogaster
Enbo Ma, … , Tian Xu, Gabriel G. Haddad
Enbo Ma, … , Tian Xu, Gabriel G. Haddad
Published March 15, 2001
Citation Information: J Clin Invest. 2001;107(6):685-693. https://doi.org/10.1172/JCI11625.
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Article

Mutation in pre-mRNA adenosine deaminase markedly attenuates neuronal tolerance to O2 deprivation in Drosophila melanogaster

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Abstract

O2 deprivation can produce many devastating clinical conditions such as myocardial infarct and stroke. The molecular mechanisms underlying the inherent tissue susceptibility or tolerance to O2 lack are, however, not well defined. Since the fruit fly, Drosophila melanogaster, is extraordinarily tolerant to O2 deprivation, we have performed a genetic screen in the Drosophila to search for loss-of-function mutants that are sensitive to low O2. Here we report on the genetic and molecular characterization of one of the genes identified from this screen, named hypnos-2. This gene encodes a Drosophila pre-mRNA adenosine deaminase (dADAR) and is expressed almost exclusively in the adult central nervous system. Disruption of the dADAR gene results in totally unedited sodium (Para), calcium (Dmca1A), and chloride (DrosGluCl-α) channels, a very prolonged recovery from anoxic stupor, a vulnerability to heat shock and increased O2 demands, and neuronal degeneration in aged flies. These data clearly demonstrate that, through the editing of ion channels as targets, dADAR, for which there are mammalian homologues, is essential for adaptation to altered environmental stresses such as O2 deprivation and for the prevention of premature neuronal degeneration.

Authors

Enbo Ma, Xiang-Qun Gu, Xiaohui Wu, Tian Xu, Gabriel G. Haddad

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Figure 1

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Complementation test for genetic mapping of hypnos-2P. The hypnos-2P mut...
Complementation test for genetic mapping of hypnos-2P. The hypnos-2P mutation was located previously between genetic markers y (1B1) and cv (5B) on the X chromosome (10). To further map the cytological location of hypnos-2P mutation, genetic crosses between hypnos-2P flies and other deficiencies in this region were carried out (a). The recovery time after 5-minute anoxia was significantly prolonged in the hypnos-2P–mutant flies when compared with either its heterozygotes (hypnos-2P/+) or control (C-S) flies (P < 0.0001). The average recovery time (mean ± SE) for hypnos-2P, heterozygote (hypnos-2P/+), and C-S is 615.8 ± 23.5 seconds (n = 58), 321.1 ± 7 seconds (n = 51), and 324 ± 5.8 seconds (n = 204), respectively. Since the heterozygote female flies (hypnos-2P/+) have a distribution similar to that of the wild-type flies, this mutation is recessive. It should be noted that there are two alleles at the hypnos-2 locus (hypnos-2L and hypnos-2P), but we have focused on hypnos-2P in this work. Our studies showed that hypnos-2P flies failed to complement with the deletions of either df(1)A94 (1E3-2B15) or df(1)st472 (2B6-2B12), but they complemented with df(1)S39 (1E1-2B5). AP < 0.0001. (b) Schematic presentation of cytological locations of three deficiencies used in the complementation tests. The results from these complementation tests indicate that the hypnos-2P mutation is located in the region between 2B6 and 2B12 on the X chromosome.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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