Adar3 Is Involved in Learning and Memory in Mice

Mladenova, Dessislava; Barry, Guy; Konen, Lyndsey M.; Pineda, Sandy S.; Guennewig, Boris; Avesson, Lotta; Zinn, Raphael; Schönrock, Nicole; Bitar, Mainá; Jonkhout, Nicky; Crumlish, Lauren; Kaczorowski, Dominik C.; Gong, Andrew; Pinese, Mark; Franco, Glória Regina; Walkley, Carl R.; Vissel, Bryce; Mattick, John S.

doi:10.3389/fnins.2018.00243

Cited by 58 publications

(38 citation statements)

References 80 publications

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“…RNA editing by ADAR2 is metabolically regulated, for example in pancreatic islets and beta cells (116). Adar3 knockout mice are born following predicted Mendelian ratios and do not display any atypical developmental characteristics (117). Mice with the Adar3 gene disrupted by deletion of exon 3 (which includes the two copies of the dsRNA-binding domain, Fig.…”

Section: Mda5-mavsmentioning

confidence: 99%

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Adenosine deaminase acting on RNA (ADAR1), a suppressor of double-stranded RNA–triggered innate immune responses

Samuel

2019

Journal of Biological Chemistry

125

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Herbert “Herb” Tabor, who celebrated his 100th birthday this past year, served the Journal of Biological Chemistry as a member of the Editorial Board beginning in 1961, as an Associate Editor, and as Editor-in-Chief for 40 years, from 1971 until 2010. Among the many discoveries in biological chemistry during this period was the identification of RNA modification by C6 deamination of adenosine (A) to produce inosine (I) in double-stranded (ds) RNA. This posttranscriptional RNA modification by adenosine deamination, known as A-to-I RNA editing, diversifies the transcriptome and modulates the innate immune interferon response. A-to-I editing is catalyzed by a family of enzymes, adenosine deaminases acting on dsRNA (ADARs). The roles of A-to-I editing are varied and include effects on mRNA translation, pre-mRNA splicing, and micro-RNA silencing. Suppression of dsRNA-triggered induction and action of interferon, the cornerstone of innate immunity, has emerged as a key function of ADAR1 editing of self (cellular) and nonself (viral) dsRNAs. A-to-I modification of RNA is essential for the normal regulation of cellular processes. Dysregulation of A-to-I editing by ADAR1 can have profound consequences, ranging from effects on cell growth and development to autoimmune disorders.

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Section: Mda5-mavsmentioning

confidence: 99%

“…Mice with the Adar3 gene disrupted by deletion of exon 3 (which includes the two copies of the dsRNA-binding domain, Fig. 1, lower panel) do, however, show deficits in learning and memory (117).…”

Section: Mda5-mavsmentioning

confidence: 99%

Adenosine deaminase acting on RNA (ADAR1), a suppressor of double-stranded RNA–triggered innate immune responses

Samuel

2019

Journal of Biological Chemistry

125

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“…Mammals express three ADAR proteins: ADAR1, ADAR2 and ADAR3 (encoded by Adar , Adarb1 and Adarb2 , respectively). ADAR1 and ADAR2 have both demonstrated editing activity in vitro and in vivo [ 38 – 40 ], while ADAR3 does not show editing activity in vitro and Adarb2 −/− (ADAR3 −/− ) mice do not show alterations in editing [ 41 , 42 ].…”

Section: Mammalian A-to-i Rna Editing and Adenosine Deaminase Acting mentioning

confidence: 99%

“…Adarb2 −/− (ADAR3 −/− ) do not have any developmental defects [ 42 ]. They have recently been described to have increased anxiety and deficits in short- and long-term memory formation, which are dependent on hippocampus function.…”

Section: The Application Of Genetics To Understand the In Vmentioning

confidence: 99%

What do editors do? Understanding the physiological functions of A-to-I RNA editing by adenosine deaminase acting on RNAs

Heraud-Farlow

Walkley

2020

Open Biol.

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Adenosine-to-inosine (A-to-I) editing is a post-transcriptional modification of RNA which changes its sequence, coding potential and secondary structure. Catalysed by the adenosine deaminase acting on RNA (ADAR) proteins, ADAR1 and ADAR2, A-to-I editing occurs at approximately 50 000–150 000 sites in mice and into the millions of sites in humans. The vast majority of A-to-I editing occurs in repetitive elements, accounting for the discrepancy in total numbers of sites between species. The species-conserved primary role of editing by ADAR1 in mammals is to suppress innate immune activation by unedited cell-derived endogenous RNA. In the absence of editing, inverted paired sequences, such as Alu elements, are thought to form stable double-stranded RNA (dsRNA) structures which trigger activation of dsRNA sensors, such as MDA5. A small subset of editing sites are within coding sequences and are evolutionarily conserved across metazoans. Editing by ADAR2 has been demonstrated to be physiologically important for recoding of neurotransmitter receptors in the brain. Furthermore, changes in RNA editing are associated with various pathological states, from the severe autoimmune disease Aicardi-Goutières syndrome, to various neurodevelopmental and psychiatric conditions and cancer. However, does detection of an editing site imply functional importance? Genetic studies in humans and genetically modified mouse models together with evolutionary genomics have begun to clarify the roles of A-to-I editing in vivo . Furthermore, recent developments suggest there may be the potential for distinct functions of editing during pathological conditions such as cancer.

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“…ADAR2 has both RNA binding and RNA editing domains and is best known for its role in the, editing of the ionotropic glutamate receptor 2 (GluR2) subunit 8 , which is essential for neuronal plasticity 9 . Finally, ADAR3 has an RNA binding domain and, although lacking in enzymatic activity 10 , recent work indicates that Adar3 knockout leads to impaired fear memory in mice by altering a small percentage of known RNA editing targets 11 .…”

Section: Introductionmentioning

confidence: 99%

Dynamic DNA structure states interact with the RNA editing enzyme ADAR1 to modulate fear extinction memory

Zhao

et al. 2019

Preprint

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RNA modification has recently emerged as an important mechanism underlying gene diversity linked to behavioral regulation. The conversion of adenosine to inosine by the ADAR family of enzymes is a particularly important RNA modification as it impacts the physiological readout of protein-coding genes. However, not all variants of ADAR appear to act solely on RNA. ADAR1 binds directly to DNA when it is in a non-canonical, left handed, "Z" conformation, but little is known about the functional relevance of this interaction. Here we report that ADAR1 binds to Z-DNA in an activity-dependent manner and that fear extinction learning leads to increased ADAR1 occupancy at DNA repetitive elements, with targets adopting a Z-DNA structure at sites of ADAR1 recruitment.Knockdown of ADAR1 leads to an inability to modify a previously acquired memory trace and this is associated with a concomitant change in DNA structure and a decrease in RNA editing. These findings suggest a novel mechanism of learning-induced gene regulation whereby ADAR1 physically interacts with Z-DNA in order to mediate its effect on RNA, and both are required for memory flexibility following fear extinction learning.

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Adar3 Is Involved in Learning and Memory in Mice

Cited by 58 publications

References 80 publications

Adenosine deaminase acting on RNA (ADAR1), a suppressor of double-stranded RNA–triggered innate immune responses

Adenosine deaminase acting on RNA (ADAR1), a suppressor of double-stranded RNA–triggered innate immune responses

What do editors do? Understanding the physiological functions of A-to-I RNA editing by adenosine deaminase acting on RNAs

Dynamic DNA structure states interact with the RNA editing enzyme ADAR1 to modulate fear extinction memory

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