Mechanistically Distinct Mouse Models for CRX-Associated Retinopathy

Tran, Nicholas M.; Alan, Zhang; Zhang, Xiaodong; Huecker, Julie; Hennig, Anne K.; Chen, Shiming

doi:10.1371/journal.pgen.1004111

Cited by 57 publications

(193 citation statements)

References 62 publications

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“…As previously observed, many genes are misregulated in absence of CRX in the retina including genes that are direct targets of MEF2D (Figure 4A, B, E, S4C & Table S2) (Hsiau et al, 2007; Tran et al, 2014). Next, we analyzed CRX ChIP-Seq data (Corbo et al, 2010) for overlap with MEF2D ChIP-Seq to determine if CRX co-regulates MEF2D target genes by co-binding to shared target gene enhancers and promoters.…”

Section: Resultssupporting

confidence: 76%

MEF2D Drives Photoreceptor Development through a Genome-wide Competition for Tissue-Specific Enhancers

Andzelm

Cherry

Harmin

et al. 2015

Neuron

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Summary Organismal development requires the precise coordination of genetic programs to regulate cell fate and function. MEF2 transcription factors (TFs) play essential roles in this process but how these broadly expressed factors contribute to the generation of specific cell types during development is poorly understood. Here we show that despite being expressed in virtually all mammalian tissues, in the retina MEF2D binds to retina-specific enhancers and controls photoreceptor cell development. MEF2D achieves specificity by cooperating with a retina-specific factor CRX, which recruits MEF2D away from canonical MEF2 binding sites, and redirects it to retina-specific enhancers that lack the consensus MEF2-binding sequence. Once bound to retina-specific enhancers, MEF2D and CRX co-activate the expression of photoreceptor-specific genes that are critical for retinal function. These findings demonstrate that broadly expressed TFs acquire specific functions through competitive recruitment to enhancers by tissue-specific TFs, and through selective activation of these enhancers to regulate tissue-specific genes.

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Section: Resultssupporting

confidence: 76%

MEF2D Drives Photoreceptor Development through a Genome-wide Competition for Tissue-Specific Enhancers

Andzelm

Cherry

Harmin

et al. 2015

Neuron

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“…Various transcriptional factors, such as Crx, facilitate the expression of opsin, which is essential for photoreceptor functions (28,29). Interestingly, taurine, a known cysteine derivative, is transported by Slc6a6 into photoreceptors to enhance the expression of many essential genes (15); however, overexpression of two essential genes, Cngb1 and Rom1, has been reported to result in attenuated scotopic ERG and photopic ERG responses, respectively (25,26).…”

Section: Discussionmentioning

confidence: 99%

miR-183/96 plays a pivotal regulatory role in mouse photoreceptor maturation and maintenance

Xiang

Chen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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MicroRNAs (miRNAs) are known to be essential for retinal maturation and functionality; however, the role of the most abundant miRNAs, the miR-183/96/182 cluster (miR-183 cluster), in photoreceptor cells remains unclear. Here we demonstrate that ablation of two components of the miR-183 cluster, miR-183 and miR-96, significantly affects photoreceptor maturation and maintenance in mice. Morphologically, early-onset dislocated cone nuclei, shortened outer segments and thinned outer nuclear layers are observed in the miR-183/96 double-knockout (DKO) mice. Abnormal photoreceptor responses, including abolished photopic electroretinography (ERG) responses and compromised scotopic ERG responses, reflect the functional changes in the degenerated retina. We further identify Slc6a6 as the cotarget of miR-183 and miR-96. The expression level of Slc6a6 is significantly higher in the DKO mice than in the wild-type mice. In contrast, Slc6a6 is down-regulated by adenoassociated virus-mediated overexpression of either miR-183 or miR-96 in wild-type mice. Remarkably, both silencing and overexpression of Slc6a6 in the retina are detrimental to the electrophysiological activity of the photoreceptors in response to dim light stimuli. We demonstrate that miR-183/96-mediated fine-tuning of Slc6a6 expression is indispensable for photoreceptor maturation and maintenance, thereby providing insight into the epigenetic regulation of photoreceptors in mice.miR-183/96/182 cluster | regulation | photoreceptor | taurine transporter | degeneration M icroRNAs (miRNAs) are known to act as important epigenetic coordinators during posttranscriptional processing via the regulation of hundreds of target genes with great temporal and spatial precision (1-3). Wholesale and individual disruption of miRNAs has been shown to result in various retinal defects and other sensorial diseases (4-6). The retinal photoreceptor is a type of ciliated neuron in which the miR-183 cluster represents the most highly expressed miRNAs. Although different mouse models have been generated to determine the roles of the miR-183 cluster, many previous studies have used nonspecific or incomplete miRNA depletion to examine the effects of eliminating specific miRNAs on photoreceptor degeneration (5, 6). Little is known about the impact of a "null" miR-183/96/182 model in vivo.A recent study of miR-182 and miR-183 identified these two miRNAs as essential for the maturation and function of cone photoreceptors (7). In addition, their expression is necessary and sufficient for the formation of cone outer segments (OSs) (7). Another study likewise showed that inactivation of the miR-183 cluster by gene trapping resulted in abnormal electroretinography (ERG) responses, progressive synaptic defects, and progressive retinal degeneration (4). Other investigators have reported that impairment of miR-96 resulted in hair cell death in the inner ear, as well as progressive hearing loss in zebrafish, mice, and humans (8-10). Notwithstanding these findings, however, our understanding of the re...

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“…The mutant proteins p.E168d1, p.E168d2, p.A196d4, and p.G217d1 all lose the ability to transactivate the promoter of Rhodopsin (Chen et al, ). Additionally, p.E168d2 maintains DNA binding activity and interferes with WT CRX function (Tran et al, ). p.I138 fs48 also shows antimorphic activity on target gene expression in Drosophila Rh5 rescue experiments (Terrell et al, ).…”

Section: Classification Of Reported Human Crx Mutationsmentioning

confidence: 99%

Mechanisms of blindness: Animal models provide insight into distinct CRX‐associated retinopathies

Tran

Chen

2014

Developmental Dynamics

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The homeodomain transcription factor CRX is a crucial regulator of mammalian photoreceptor gene expression. Mutations in the human CRX gene are associated with dominant inherited retinopathies Retinitis Pigmentosa (RP), Cone-Rod Dystrophy (CoRD) and Leber Congenital Amaurosis (LCA), of varying severity. In vitro and in vivo assessment of mutant CRX proteins have revealed pathogenic mechanisms for several mutations, but no comprehensive mutation-disease correlation has yet been reported. Here we describe four different classes of disease-causing CRX mutations, characterized by mutation type, pathogenetic mechanism, and the molecular activity of the mutant protein: I) hypomorphic missense mutations with reduced DNA binding, II) antimorphic missense mutations with variable DNA binding, III) antimorphic frameshift/nonsense mutations with intact DNA binding and IV) antimorphic frameshift mutations with reduced DNA binding. Mammalian models representing three of these classes have been characterized. Models carrying Class I mutations display a mild dominant retinal phenotype and recessive LCA, while models carrying Class III and IV mutations display characteristically distinct dominant LCA phenotypes. These animal models also reveal unexpected pathogenic mechanisms underlying CRX-associated retinopathies. The complexity of genotype-phenotype correlation for CRX-associated diseases highlights the value of developing comprehensive 'true-to-disease' animal models for understanding pathologic mechanisms and testing novel therapeutic approaches.

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Mechanistically Distinct Mouse Models for CRX-Associated Retinopathy

Cited by 57 publications

References 62 publications

MEF2D Drives Photoreceptor Development through a Genome-wide Competition for Tissue-Specific Enhancers

MEF2D Drives Photoreceptor Development through a Genome-wide Competition for Tissue-Specific Enhancers

miR-183/96 plays a pivotal regulatory role in mouse photoreceptor maturation and maintenance

Mechanisms of blindness: Animal models provide insight into distinct CRX‐associated retinopathies

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