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Series GSE52006 Query DataSets for GSE52006
Status Public on Jan 13, 2014
Title OTX2 loss causes rod differentiation defect in CRX-associated congenital blindness
Organism Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Leber congenital amaurosis (LCA) includes congenital or early-onset blinding diseases, characterized by vision loss together with nystagmus and nonrecordable electroretinogram (ERG). At least 19 genes are associated with LCA. While most LCA is recessive, mutations in the homeodomain transcription factor gene CRX lead to autosomal dominant LCA. The mechanism of CRX-LCA is not understood. Here, we report a new spontaneous mouse mutant carrying a frameshift mutation in Crx (CrxRip). We show that, unlike Crx-/- mouse retina, the dominant Crx c.763del1 mutation in CrxRip results in congenital blindness with complete loss of ERG, yet the photoreceptors do not degenerate. Dominant CRX frameshift mutations associated with LCA mimic the CrxRip phenotype that can be rescued by Crx. RNA-Seq profiling reveals progressive and complete loss of rod differentiation factor Nrl in CrxRip, while residual Nrl remains in Crx-/- retina. Moreover, Nrl partially restores the rod phenotype in CrxRip/+ mice. We show that the binding of Otx2 to Nrl promoter is obliterated in CrxRip mutant, and ectopic Otx2 can rescue the rod phenotype. Therefore, Otx2 is required to maintain Nrl expression in developing rods to consolidate rod fate. Our studies provide the mechanism of congenital blindness caused by dominant CRX mutations and should assist in therapeutic design.
Overall design Retinal samples were harvested from WT, CrxRip/+, CrxRip/Rip, Crx-/- and Nrl-/- retina at postnatal days 2 and 21 for whole transcriptome sequencing (RNAseq). Each sample included 2 independent frozen retina and experiments were performed in duplicates. RNA-seq transcriptome libraries were constructed from 1 μg of total RNA.
Contributor(s) Roger JE, Hiriyanna A, Gotoh N, Hao H, Cheng DF, Ratnapriya R, Kautzmann MI, Chang B, Swaroop A
Citation(s) 24382353
Submission date Nov 01, 2013
Last update date May 15, 2019
Contact name Jerome Eric Roger
Phone +33169156835
Organization name CNRS-Universite Paris Sud
Department CERTO
Lab Neuro-PSI
Street address 151 Route de la Rotonde, Campus CEA Saclay - Bat 151
City Saclay
State/province Please select
ZIP/Postal code 91400
Country France
Platforms (1)
GPL11002 Illumina Genome Analyzer IIx (Mus musculus)
Samples (20)
GSM1257264 P2_WT_rep1
GSM1257265 P2_WT_rep2
GSM1257266 P2_Het_rep1
BioProject PRJNA226093
SRA SRP032458

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Supplementary file Size Download File type/resource
GSE52006_P21_NE2_APV005_FC2.txt.gz 143.7 Kb (ftp)(http) TXT
GSE52006_P2_NE2_APV005_FC2.txt.gz 52.9 Kb (ftp)(http) TXT
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Processed data are available on Series record

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