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Published on: September 23, 2015
A-to-I pre-mRNA editing of the serotonin 2C receptor: comparisons among inbred mouse strains
Yunzhi Du1, Muriel T Davisson, Karen Kafadar
1Eleanor Roosevelt Institute at the University of Denver, CO 80206, USA.
Abstract:
The serotonin receptor 5HT2CR pre-mRNA is subject to adenosine deamination (RNA editing) at five residues located within a 15 nucleotide stretch of the coding region. Such changes of adenosine to inosine (A-to-I) can produce 32 mRNA variants, encoding 24 different protein isoforms, some of which vary in biochemical and pharmacological properties. Because serotonin mediates diverse neurological processes relevant to behavior and because inbred mouse strains vary in their responses to tests of learning and behavior, we have examined the A-to-I editing patterns of the 5HT2CR mRNA in whole brains from eight mouse strains. By sequencing approximately 100 clones from individual mice, we generated detailed information on levels of editing at each site and patterns of editing that identify a total of 28 mRNA and 20 protein isoforms. Significant differences between individuals from different strains were found in total editing frequency, in the proportion of transcripts with 1 and 4 edited sites, in editing frequency at the A, B, E and D sites, in amino acid frequencies at positions 157 and 161, and in subsets of major protein isoforms. Primer extension assays were used to show that individuals within strains (six C3H.B-+rd1 and four 129SvImrJ) displayed no significant differences in any feature. These findings suggest that genetic background contributes to subtle variation in 5HT2CR mRNA editing patterns which may have consequences for pharmacological treatments and behavioral testing.
Insights
Genetic background influences serotonin receptor 5HT2CR mRNA editing patterns in mice. These variations in adenosine-to-inosine (A-to-I) RNA editing may impact neurological processes and drug responses.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Serotonin receptor 5HT2CR pre-mRNA undergoes adenosine deamination (RNA editing) at five sites.
- A-to-I RNA editing generates diverse mRNA and protein isoforms with potentially different properties.
- Inbred mouse strains exhibit variations in learning and behavior, suggesting genetic influences on neurological processes.
Purpose of the Study:
- To investigate the A-to-I RNA editing patterns of 5HT2CR mRNA across eight different inbred mouse strains.
- To determine if genetic background influences the extent and patterns of 5HT2CR mRNA editing.
- To explore potential correlations between RNA editing variations and neurological functions or drug responses.
Main Methods:
- Sequencing of approximately 100 mRNA clones per mouse brain to analyze A-to-I editing at specific sites.
- Quantification of editing levels at individual sites and identification of resulting mRNA and protein isoforms.
- Primer extension assays to assess intra-strain variability in editing patterns.
Main Results:
- Significant differences in total editing frequency and editing at specific sites (A, B, E, D) were observed between mouse strains.
- Variations in the proportion of transcripts with 1 and 4 edited sites were identified across strains.
- Strain-specific differences were found in amino acid frequencies and major protein isoform subsets, while intra-strain variability was minimal.
Conclusions:
- Genetic background significantly contributes to subtle variations in 5HT2CR mRNA editing patterns.
- These observed editing differences may have implications for understanding mouse behavior and responses to pharmacological treatments.
- Further research is warranted to elucidate the functional consequences of strain-specific RNA editing in the 5HT2CR gene.
