Graded gene expression changes determine phenotype severity in mouse models of CRX-associated retinopathies.
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.
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, MO, USA.|Molecular Genetics and Genomics Graduate Program, Division of Biology & Biomedical Sciences, Washington University School of Medicine, Saint Louis, MO, USA.
Philip A
PA
Ruzycki
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, MO, USA.|Molecular Genetics and Genomics Graduate Program, Division of Biology & Biomedical Sciences, Washington University School of Medicine, Saint Louis, MO, USA.|Current address: Department of Molecular and Cellular Biology, Harvard University, NW 335.30, 52 Oxford St, Cambridge, MA, 02138, USA.
Nicholas M
NM
Tran
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, MO, USA.
Vladimir J
VJ
Kefalov
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, MO, USA.
Alexander V
AV
Kolesnikov
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, MO, USA. chen@vision.wustl.edu.|Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO, USA. chen@vision.wustl.edu.|Molecular Genetics and Genomics Graduate Program, Division of Biology & Biomedical Sciences, Washington University School of Medicine, Saint Louis, MO, USA. chen@vision.wustl.edu.
Shiming
S
Chen
D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism; D044127:Epigenesis, Genetic; D005136:Eye Proteins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics*; D006720:Homozygote; D055537:Light Signal Transduction / Q000235:genetics; D051379:Mice; D009154:Mutation; D010641:Phenotype; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism; D012160:Retina / Q000254:growth & development / Q000378:metabolism; D012162:Retinal Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015534:Trans-Activators / Q000235:genetics*
D050976:Basic-Leucine Zipper Transcription Factors; D005136:Eye Proteins; D006657:Histones; D018398:Homeodomain Proteins; C084884:Nrl protein, mouse; D015534:Trans-Activators; C109288:cone rod homeobox protein