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Series GSE82068 Query DataSets for GSE82068
Status Public on Dec 31, 2016
Title Negative allosteric modulation of mGluR5 partially corrects pathophysiology in a mouse model of Rett Syndrome
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Rett syndrome is caused by mutations in the gene encoding methyl-CpG binding protein 2 (MECP2), an epigenetic regulator of mRNA transcription. Here we report a test of the hypothesis of shared pathophysiology of Rett syndrome and fragile X, another monogenic cause of autism and intellectual disability. In fragile X, the loss of the mRNA translational repressor FMRP leads to exaggerated protein synthesis downstream of metabotropic glutamate receptor 5 (mGluR5). We found that mGluR5- and protein synthesis-dependent synaptic plasticity is similarly altered in area CA1 of Mecp2 KO mice. CA1 pyramidal cell-type-specific, genome-wide profiling of ribosome-bound mRNAs was performed in wild-type and Mecp2 KO hippocampal CA1 neurons to reveal the MeCP2-regulated ‘translatome’. We found significant overlap between ribosome-bound transcripts overexpressed in the Mecp2 KO and FMRP mRNA targets. These tended to encode long genes that are functionally related to either cytoskeleton organization or the development of neuronal connectivity. In the Fmr1 KO mouse, chronic treatment with mGluR5 negative allosteric modulators (NAMs) has been shown to ameliorate many mutant phenotypes by correcting excessive protein synthesis. In the Mecp2 KO mice we found that mGluR5 NAM treatment significantly reduces the level of overexpressed ribosome-associated transcripts, particularly those that are also FMRP targets. Some Rett phenotypes were also ameliorated by treatment, most notably hippocampal cell size and life span. Together, these results suggest a potential mechanistic link between MeCP2-mediated transcription regulation and mGluR5/FMRP-mediated protein translation regulation through co-regulation of a subset of genes relevant to synaptic functions.
Overall design TRAP-seq analysis of the effect of negative modulator of mGluR5 on the CA1 neurons (marked by Cck-EGFP-L10a) of a mouse model of Rett syndrome
Contributor(s) Tao J, Wu H, Bear M
Citation(s) 27881780
Submission date May 31, 2016
Last update date May 15, 2019
Contact name Hao Wu
Phone 617-713-8660
Organization name Harvard Medical School/HHMI
Department Genetics
Lab Yi Zhang
Street address 149G Warren Alpert Building, 200 Longwood Avenue
City Boston
State/province Massachusetts
ZIP/Postal code 02115
Country USA
Platforms (2)
GPL17021 Illumina HiSeq 2500 (Mus musculus)
GPL19057 Illumina NextSeq 500 (Mus musculus)
Samples (15)
GSM2182998 Mecp2_wt_p37_IP
GSM2182999 Mecp2_wt_p37_Input
GSM2183000 Mecp2_wt_p56_IP
BioProject PRJNA323858
SRA SRP075917

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SOFT formatted family file(s) SOFTHelp
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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE82068_DESeq2_htseq-counts_IP.vs.input.txt.gz 366.0 Kb (ftp)(http) TXT
GSE82068_DESeq2_htseq-counts_Veh.vs.CTEP.txt.gz 486.9 Kb (ftp)(http) TXT
GSE82068_DESeq2_htseq-counts_wt.vs.ko.txt.gz 734.2 Kb (ftp)(http) TXT
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Processed data are available on Series record

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