The transcription factor GTF2IRD1 regulates the topology and function of photoreceptors by modulating photoreceptor gene expression across the retina.
The mechanisms that specify photoreceptor cell-fate determination, especially as regards to short-wave-sensitive (S) versus medium-wave-sensitive (M) cone identity, and maintain their nature and function, are not fully understood. Here we report the importance of general transcription factor II-I repeat domain-containing protein 1 (GTF2IRD1) in maintaining M cone cell identity and function as well as rod function. In the mouse, GTF2IRD1 is expressed in cell-fate determined photoreceptors at postnatal day 10. GTF2IRD1 binds to enhancer and promoter regions in the mouse rhodopsin, M- and S-opsin genes, but regulates their expression differentially. Through interaction with the transcription factors CRX and thyroid hormone receptor β 2, it enhances M-opsin expression, whereas it suppresses S-opsin expression; and with CRX and NRL, it enhances rhodopsin expression. In an apparent paradox, although GTF2IRD1 is widely expressed in multiple cell types across the retina, knock-out of GTF2IRD1 alters the retinal expression of only a limited number of annotated genes. Interestingly, however, the null mutation leads to altered topology of cone opsin expression in the retina, with aberrant S-opsin overexpression and M-opsin underexpression in M cones. Gtf2ird1-null mice also demonstrate abnormal M cone and rod electrophysiological responses. These findings suggest an important role for GTF2IRD1 in regulating the level and topology of rod and cone gene expression, and in maintaining normal retinal function.
Department of Ophthalmology, Wilmer Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231.
Tomohiro
http://orcid.org/0000-0002-6668-1246
T
Masuda
Departments of Ophthalmology and Visual Sciences, and.
Xiaodong
X
Zhang
Department of Ophthalmology, Wilmer Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231.
Cindy
C
Berlinicke
Department of Ophthalmology, Wilmer Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231.
Jun
J
Wan
Department of Ophthalmology, Wilmer Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231.
Anitha
A
Yerrabelli
Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Elizabeth A
EA
Conner
Translational Research in Retinal and Macular Degeneration, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland 20892.
Sten
S
Kjellstrom
Translational Research in Retinal and Macular Degeneration, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland 20892.
Ronald
R
Bush
Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Snorri S
SS
Thorgeirsson
Neurobiology-Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892.
Anand
http://orcid.org/0000-0002-1975-1141
A
Swaroop
Departments of Ophthalmology and Visual Sciences, and Developmental Biology, Washington University School of Medicine, St Louis, Missouri 63110.
Shiming
S
Chen
Department of Ophthalmology, Wilmer Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, Departments of Molecular Biology and Genetics, Neuroscience, Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, and Institut de la Vision, University Pierre and Marie Curie, Paris 75012, France dzack@jhmi.edu.
Donald J
http://orcid.org/0000-0002-7966-1973
DJ
Zack
D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000378:metabolism; D004596:Electroretinography; D005136:Eye Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology*; D055355:Opsins / Q000378:metabolism; D061251:Primary Cell Culture; D012160:Retina / Q000378:metabolism*; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism / Q000502:physiology*; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism / Q000502:physiology*; D012243:Rhodopsin / Q000378:metabolism; D037042:Thyroid Hormone Receptors beta / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*
D050976:Basic-Leucine Zipper Transcription Factors; D005136:Eye Proteins; C486558:Gtf2ird1 protein, mouse; D018398:Homeodomain Proteins; D009124:Muscle Proteins; C084884:Nrl protein, mouse; D009687:Nuclear Proteins; D055355:Opsins; D037042:Thyroid Hormone Receptors beta; D015534:Trans-Activators; C109288:cone rod homeobox protein; D012243:Rhodopsin
gene expression; opsin; photoreceptor; retina; transcription factor