A-to-I Pre-mRNA Editing in Drosophila Is Primarily Involved in Adult Nervous System Function and Integrity

Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington 06030, USA.
Cell (Impact Factor: 32.24). 09/2000; 102(4):437-49. DOI: 10.1016/S0092-8674(00)00049-0
Source: PubMed


Specific A-to-I RNA editing, like that seen in mammals, has been reported for several Drosophila ion channel genes. Drosophila possesses a candidate editing enzyme, dADAR. Here, we describe dADAR deletion mutants that lack ADAR activity in extracts. Correspondingly, all known Drosophila site-specific RNA editing (25 sites in three ion channel transcripts) is abolished. Adults lacking dADAR are morphologically wild-type but exhibit extreme behavioral deficits including temperature-sensitive paralysis, locomotor uncoordination, and tremors which increase in severity with age. Neurodegeneration accompanies the increase in phenotypic severity. Surprisingly, dADAR mutants are not short-lived. Thus, A-to-I editing of pre-mRNAs in Drosophila acts predominantly through nervous system targets to affect adult nervous system function, integrity, and behavior.

Download full-text


Available from: Liam P Keegan, Oct 04, 2015
5 Reads
  • Source
    • "tem undergo A - to - I editing , and loss of editing results in extreme behavioral defects ( Jepson and Reenan , 2009 ; Jepson et al . , 2011 ; Jin et al . , 2007 ; Jones et al . , 2009 ; Maldonado et al . , 2013 ; Palladino et al . , 2000 ) . Eleven A - to - I editing sites have been identified in the DmNa v transcript ( Hanrahan et al . , 2000 ; Palladino et al . , 2000 ; Reenan et al . , 2000 ; Rieder et al . , 2013 ) . The actual number of RNA editing sites may be much greater , because the transcript region examined in these studies represents only a portion of the complete DmNa v open reading frame . Nine of the eleven editing events result in amino acid changes . Some of these RNA editing sites ar"
    [Show abstract] [Hide abstract]
    ABSTRACT: Voltage-gated sodium channels are essential for the initiation and propagation of the action potential in neurons and other excitable cells. Because of their critical roles in electrical signaling, sodium channels are targets of a variety of naturally occurring and synthetic neurotoxins, including several classes of insecticides. This review is intended to provide an update on the molecular biology of insect sodium channels and the molecular mechanism of pyrethroid resistance. Although mammalian and insect sodium channels share fundamental topological and functional properties, most insect species carry only one sodium channel gene, compared to multiple sodium channel genes found in each mammalian species. Recent studies showed that two posttranscriptional mechanisms, alternative splicing and RNA editing, are involved in generating functional diversity of sodium channels in insects. More than 50 sodium channel mutations have been identified to be responsible for or associated with knockdown resistance (kdr) to pyrethroids in various arthropod pests and disease vectors. Elucidation of molecular mechanism of kdr led to the identification of dual receptor sites of pyrethroids on insect sodium channels. Most of the kdr mutations appear to be located within or close to the two receptor sites. The accumulating knowledge of insect sodium channels and their interactions with insecticides provides a foundation for understanding the neurophysiology of sodium channels in vivo and the development of new and safer insecticides for effective control of arthropod pests and human disease vectors.
    Insect biochemistry and molecular biology 04/2014; 50(1). DOI:10.1016/j.ibmb.2014.03.012 · 3.45 Impact Factor
  • Source
    • "A-to-I RNA editing plays an essential role in brain development in both Drosophila and mammals [16]–[18]. In Drosophila, several genes involved in synaptic vesicle release machinery are targets of the dADAR enzyme (e.g. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Oligophrenin-1 (OPHN1) encodes for a Rho-GTPase-activating protein, important for dendritic morphogenesis and synaptic function. Mutations in this gene have been identified in patients with X-linked intellectual disability associated with cerebellar hypoplasia. ADAR enzymes are responsible for A-to-I RNA editing, an essential post-transcriptional RNA modification contributing to transcriptome and proteome diversification. Specifically, ADAR2 activity is essential for brain development and function. Herein, we show that the OPHN1 transcript undergoes post-transcriptional modifications such as A-to-I RNA editing and alternative splicing in human brain and other tissues. We found that OPHN1 editing is detectable already at the 18th week of gestation in human brain with a boost of editing at weeks 20 to 33, concomitantly with OPHN1 expression increase and the appearance of a novel OPHN1 splicing isoform. Our results demonstrate that multiple post-transcriptional events occur on OPHN1, a gene playing an important role in brain function and development.
    PLoS ONE 03/2014; 9(3):e91351. DOI:10.1371/journal.pone.0091351 · 3.23 Impact Factor
  • Source
    • "A-to-I editing in Drosophila is catalyzed by a single neurally enriched enzyme, ADAR, which plays an important role in the maintenance of neuronal homeostasis (30–32). Consistent with this physiological role, adar mutant adults display numerous behavioral defects as well as age-dependent neurodegeneration (33,34). The expression levels of the adar transcript increased during metamorphosis (Figure 1B), suggesting a developmental basis for these defects, and coincided with the onset of the let-7-C transcript (Figure 1C), a locus required for the formation of the adult nervous system (23,25,29). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Adenosine deaminases acting on RNAs (ADARs) convert adenosine residues to inosines in primary microRNA (pri-miRNA) transcripts to alter the structural conformation of these precursors and the subsequent functions of the encoded microRNAs (miRNAs). Here we show that RNA editing by Drosophila ADAR modulates the expression of three co-transcribed miRNAs encoded by the evolutionarily conserved let-7-Complex (let-7-C) locus. For example, a single A-to-I change at the -6 residue of pri-miR-100, the first miRNA in this let-7-C polycistronic transcript, leads to enhanced miRNA processing by Drosha and consequently enhanced functional miR-100 both in vitro as well as in vivo. In contrast, other editing events, including one at the +43 residue of the pri-miR-125, destabilize the primary transcript and reduce the levels of all three encoded miRNAs. Consequently, loss of adar in vivo leads to reduced miR-100 but increased miR-125. In wild-type animals, the destabilizing editing events in pri-let-7-C increase during the larval-to-adult transition and are critical for the normal downregulation of all three miRNAs seen late in metamorphosis. These findings unravel a new regulatory role for ADAR and raise the possibility that ADAR mediates the differential expression characteristic of many polycistronic miRNA clusters.
    Nucleic Acids Research 02/2014; 42(8). DOI:10.1093/nar/gku145 · 9.11 Impact Factor
Show more