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Graded gene expression changes determine phenotype severity in mouse models of CRX-associated retinopathies.

Ruzycki PA, Tran NM, Kefalov VJ, Kolesnikov AV, Chen S - Genome Biol. (2015)

Bottom Line: Unlike down-regulated genes, which show a high degree of CRX binding and dynamic epigenetic profiles in normal retinas, the up-regulated cone-enriched genes do not correlate with direct activity of CRX, but instead likely reflect a change in rod cell-fate integrity.Furthermore, these analyses describe the impact of minor gene expression changes on the phenotype, as two mutants showed marginally distinguishable expression patterns but huge phenotypic differences, including distinct mechanisms of retinal degeneration.Our results implicate a threshold effect of gene expression level on photoreceptor function and survival, highlight the importance of CRX in photoreceptor subtype development and maintenance, and provide a molecular basis for phenotype variability in CRX-associated retinopathies.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, MO, USA.

ABSTRACT

Background: Mutations in the cone-rod-homeobox protein CRX are typically associated with dominant blinding retinopathies with variable age of onset and severity. Five well-characterized mouse models carrying different Crx mutations show a wide range of disease phenotypes. To determine if the phenotype variability correlates with distinct changes in CRX target gene expression, we perform RNA-seq analyses on three of these models and compare the results with published data.

Results: Despite dramatic phenotypic differences between the three models tested, graded expression changes in shared sets of genes are detected. Phenotype severity correlates with the down-regulation of genes encoding key rod and cone phototransduction proteins. Interestingly, in increasingly severe mouse models, the transcription of many rod-enriched genes decreases decrementally, whereas that of cone-enriched genes increases incrementally. Unlike down-regulated genes, which show a high degree of CRX binding and dynamic epigenetic profiles in normal retinas, the up-regulated cone-enriched genes do not correlate with direct activity of CRX, but instead likely reflect a change in rod cell-fate integrity. Furthermore, these analyses describe the impact of minor gene expression changes on the phenotype, as two mutants showed marginally distinguishable expression patterns but huge phenotypic differences, including distinct mechanisms of retinal degeneration.

Conclusions: Our results implicate a threshold effect of gene expression level on photoreceptor function and survival, highlight the importance of CRX in photoreceptor subtype development and maintenance, and provide a molecular basis for phenotype variability in CRX-associated retinopathies.

No MeSH data available.


Related in: MedlinePlus

Model of how Crx mutation-caused gene expression changes affect rod and cone development. The left panel describes the formation of cones in a subset of the Crx mutants and variable levels of those cells’ expression of phototransduction genes. The right panel shows how development of rods in all models is related to their gene expression changes. It also emphasizes the novel findings that Crx mutant rods display a graded phenotype of both the decreased expression of proper rod genes, and the mis-expression of cone genes
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Fig7: Model of how Crx mutation-caused gene expression changes affect rod and cone development. The left panel describes the formation of cones in a subset of the Crx mutants and variable levels of those cells’ expression of phototransduction genes. The right panel shows how development of rods in all models is related to their gene expression changes. It also emphasizes the novel findings that Crx mutant rods display a graded phenotype of both the decreased expression of proper rod genes, and the mis-expression of cone genes

Mentions: In summary, our RNA-seq analyses identified graded expression changes of shared gene sets in seven available mouse models for CRX-associated disease. Using the data presented and referenced in this paper [2, 21, 24], these models can be ranked as illustrated in Fig. 7, with the lightest bars representing the model with most severely affected rod and cone gene expression. This order correlates with phenotype severity by morphological and electrophysiological standards, and with changes in gene expression in rods and cones. This correlation was seen not only for down-regulated rod and cone genes encoding phototransduction components, but also for those up- and down-regulated gene sets that highlight the partial rod to cone conversion of the developing photoreceptors. The schematic also predicts the level of photoreceptor identity and function in various models. Most importantly, the different gene expression changes between some phenotypically distinct Crx mutant models (such as E168d2/+ versus E168d2neo/+) were rather modest, in contrast to their substantial impact on the disease phenotype.Fig. 7


Graded gene expression changes determine phenotype severity in mouse models of CRX-associated retinopathies.

Ruzycki PA, Tran NM, Kefalov VJ, Kolesnikov AV, Chen S - Genome Biol. (2015)

Model of how Crx mutation-caused gene expression changes affect rod and cone development. The left panel describes the formation of cones in a subset of the Crx mutants and variable levels of those cells’ expression of phototransduction genes. The right panel shows how development of rods in all models is related to their gene expression changes. It also emphasizes the novel findings that Crx mutant rods display a graded phenotype of both the decreased expression of proper rod genes, and the mis-expression of cone genes
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4556057&req=5

Fig7: Model of how Crx mutation-caused gene expression changes affect rod and cone development. The left panel describes the formation of cones in a subset of the Crx mutants and variable levels of those cells’ expression of phototransduction genes. The right panel shows how development of rods in all models is related to their gene expression changes. It also emphasizes the novel findings that Crx mutant rods display a graded phenotype of both the decreased expression of proper rod genes, and the mis-expression of cone genes
Mentions: In summary, our RNA-seq analyses identified graded expression changes of shared gene sets in seven available mouse models for CRX-associated disease. Using the data presented and referenced in this paper [2, 21, 24], these models can be ranked as illustrated in Fig. 7, with the lightest bars representing the model with most severely affected rod and cone gene expression. This order correlates with phenotype severity by morphological and electrophysiological standards, and with changes in gene expression in rods and cones. This correlation was seen not only for down-regulated rod and cone genes encoding phototransduction components, but also for those up- and down-regulated gene sets that highlight the partial rod to cone conversion of the developing photoreceptors. The schematic also predicts the level of photoreceptor identity and function in various models. Most importantly, the different gene expression changes between some phenotypically distinct Crx mutant models (such as E168d2/+ versus E168d2neo/+) were rather modest, in contrast to their substantial impact on the disease phenotype.Fig. 7

Bottom Line: Unlike down-regulated genes, which show a high degree of CRX binding and dynamic epigenetic profiles in normal retinas, the up-regulated cone-enriched genes do not correlate with direct activity of CRX, but instead likely reflect a change in rod cell-fate integrity.Furthermore, these analyses describe the impact of minor gene expression changes on the phenotype, as two mutants showed marginally distinguishable expression patterns but huge phenotypic differences, including distinct mechanisms of retinal degeneration.Our results implicate a threshold effect of gene expression level on photoreceptor function and survival, highlight the importance of CRX in photoreceptor subtype development and maintenance, and provide a molecular basis for phenotype variability in CRX-associated retinopathies.

View Article: PubMed Central - PubMed

Affiliation: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, MO, USA.

ABSTRACT

Background: Mutations in the cone-rod-homeobox protein CRX are typically associated with dominant blinding retinopathies with variable age of onset and severity. Five well-characterized mouse models carrying different Crx mutations show a wide range of disease phenotypes. To determine if the phenotype variability correlates with distinct changes in CRX target gene expression, we perform RNA-seq analyses on three of these models and compare the results with published data.

Results: Despite dramatic phenotypic differences between the three models tested, graded expression changes in shared sets of genes are detected. Phenotype severity correlates with the down-regulation of genes encoding key rod and cone phototransduction proteins. Interestingly, in increasingly severe mouse models, the transcription of many rod-enriched genes decreases decrementally, whereas that of cone-enriched genes increases incrementally. Unlike down-regulated genes, which show a high degree of CRX binding and dynamic epigenetic profiles in normal retinas, the up-regulated cone-enriched genes do not correlate with direct activity of CRX, but instead likely reflect a change in rod cell-fate integrity. Furthermore, these analyses describe the impact of minor gene expression changes on the phenotype, as two mutants showed marginally distinguishable expression patterns but huge phenotypic differences, including distinct mechanisms of retinal degeneration.

Conclusions: Our results implicate a threshold effect of gene expression level on photoreceptor function and survival, highlight the importance of CRX in photoreceptor subtype development and maintenance, and provide a molecular basis for phenotype variability in CRX-associated retinopathies.

No MeSH data available.


Related in: MedlinePlus