ZFIN ID: ZDB-PUB-151205-1
Fmrp Interacts with Adar and Regulates RNA Editing, Synaptic Density and Locomotor Activity in Zebrafish
Shamay-Ramot, A., Khermesh, K., Porath, H.T., Barak, M., Pinto, Y., Wachtel, C., Zilberberg, A., Lerer-Goldshtein, T., Efroni, S., Levanon, E.Y., Appelbaum, L.
Date: 2015
Source: PLoS Genetics   11: e1005702 (Journal)
Registered Authors: Appelbaum, Lior, Lerer-Goldshtein, Tali, Shamay-Ramot, Adi
Keywords: RNA editing, Zebrafish, Larvae, Polymerase chain reaction, Embryos, Motor neurons, Messenger RNA, RNA extraction
MeSH Terms:
  • Adenosine Deaminase/biosynthesis
  • Adenosine Deaminase/genetics*
  • Animals
  • Axons/metabolism
  • Axons/pathology
  • Disease Models, Animal
  • Fragile X Mental Retardation Protein/biosynthesis
  • Fragile X Mental Retardation Protein/genetics*
  • Fragile X Syndrome/genetics*
  • Fragile X Syndrome/pathology
  • Gene Expression Regulation, Developmental
  • Humans
  • Motor Activity/genetics
  • Neurons/metabolism
  • Neurons/pathology
  • RNA Editing/genetics
  • RNA-Binding Proteins/biosynthesis
  • RNA-Binding Proteins/genetics*
  • Synapses/metabolism
  • Synapses/pathology
  • Transcriptome/genetics
  • Zebrafish
  • Zebrafish Proteins/biosynthesis
  • Zebrafish Proteins/genetics*
PubMed: 26637167 Full text @ PLoS Genet.
Fragile X syndrome (FXS) is the most frequent inherited form of mental retardation. The cause for this X-linked disorder is the silencing of the fragile X mental retardation 1 (fmr1) gene and the absence of the fragile X mental retardation protein (Fmrp). The RNA-binding protein Fmrp represses protein translation, particularly in synapses. In Drosophila, Fmrp interacts with the adenosine deaminase acting on RNA (Adar) enzymes. Adar enzymes convert adenosine to inosine (A-to-I) and modify the sequence of RNA transcripts. Utilizing the fmr1 zebrafish mutant (fmr1-/-), we studied Fmrp-dependent neuronal circuit formation, behavior, and Adar-mediated RNA editing. By combining behavior analyses and live imaging of single axons and synapses, we showed hyperlocomotor activity, as well as increased axonal branching and synaptic density, in fmr1-/- larvae. We identified thousands of clustered RNA editing sites in the zebrafish transcriptome and showed that Fmrp biochemically interacts with the Adar2a protein. The expression levels of the adar genes and Adar2 protein increased in fmr1-/- zebrafish. Microfluidic-based multiplex PCR coupled with deep sequencing showed a mild increase in A-to-I RNA editing levels in evolutionarily conserved neuronal and synaptic Adar-targets in fmr1-/- larvae. These findings suggest that loss of Fmrp results in increased Adar-mediated RNA editing activity on target-specific RNAs, which, in turn, might alter neuronal circuit formation and behavior in FXS.