Photoreceptor cell-specific nuclear receptor explained

The photoreceptor cell-specific nuclear receptor (PNR), also known as NR2E3 (nuclear receptor subfamily 2, group E, member 3), is a protein that in humans is encoded by the NR2E3 gene.^[1] PNR is a member of the nuclear receptor super family of intracellular transcription factors.

Function

PNR is exclusively expressed in the retina. The main target genes of PNR are rhodopsin and several opsins which are essential for sight.^[2]

Structure and ligands

The crystal structure of PNR's ligand-binding domain is known. It self-dimerizes into, by default, a repressor state. Computer simulations based on this model shows that a ligand could possibly fit into PNR and switch it into a transcription activator. 13-cis retinoic acid is a known weak agonist that fits into such a pocket, but no physiologic ligand is known. Two synthetic compounds, 11A and 11B, appear to be agonists but do not go into the pocket and instead work as allosteric modulators.^[3] A more recent screening identifies another compound called photoregulin-1 (PR1) that functions as a reverse agonist, an activity possibly useful in the management of retinitis pigmentosa.^[4]

Clinical significance

Mutations in the NR2E3 gene have been linked to several inherited retinal diseases, including enhanced S-cone syndrome (ESCS),^[5] a form of retinitis pigmentosa,^[6] and Goldmann-Favre syndrome.^[7]

Further reading

• Chen F, Figueroa DJ, Marmorstein AD, Zhang Q, Petrukhin K, Caskey CT, Austin CP . Retina-specific nuclear receptor: A potential regulator of cellular retinaldehyde-binding protein expressed in retinal pigment epithelium and Müller glial cells . Proceedings of the National Academy of Sciences of the United States of America . 96 . 26 . 15149–54 . December 1999 . 10611353 . 24788 . 10.1073/pnas.96.26.15149 . 1999PNAS...9615149C . free .
• Haider NB, Jacobson SG, Cideciyan AV, Swiderski R, Streb LM, Searby C, Beck G, Hockey R, Hanna DB, Gorman S, Duhl D, Carmi R, Bennett J, Weleber RG, Fishman GA, Wright AF, Stone EM, Sheffield VC . 6 . Mutation of a nuclear receptor gene, NR2E3, causes enhanced S cone syndrome, a disorder of retinal cell fate . Nature Genetics . 24 . 2 . 127–31 . February 2000 . 10655056 . 10.1038/72777 . 19508439 .
• Rendtorff ND, Vissing H, Tümer Z, Silahtaroglu A, Tommerup N . Assignment of the NR2E3 gene to mouse chromosome 9 and to human chromosome 15q22.33-->q23 . Cytogenetics and Cell Genetics . 89 . 3–4 . 279–80 . 2000 . 10965145 . 10.1159/000015635 . 34825159 .
• Gerber S, Rozet JM, Takezawa SI, dos Santos LC, Lopes L, Gribouval O, Penet C, Perrault I, Ducroq D, Souied E, Jeanpierre M, Romana S, Frézal J, Ferraz F, Yu-Umesono R, Munnich A, Kaplan J . 6 . The photoreceptor cell-specific nuclear receptor gene (PNR) accounts for retinitis pigmentosa in the Crypto-Jews from Portugal (Marranos), survivors from the Spanish Inquisition . Human Genetics . 107 . 3 . 276–84 . September 2000 . 11071390 . 10.1007/s004390000350 . 10400.17/1708 . 2774255 . free .
• Haider NB, Naggert JK, Nishina PM . Excess cone cell proliferation due to lack of a functional NR2E3 causes retinal dysplasia and degeneration in rd7/rd7 mice . Human Molecular Genetics . 10 . 16 . 1619–26 . August 2001 . 11487564 . 10.1093/hmg/10.16.1619 . free .
• Milam AH, Rose L, Cideciyan AV, Barakat MR, Tang WX, Gupta N, Aleman TS, Wright AF, Stone EM, Sheffield VC, Jacobson SG . 6 . The nuclear receptor NR2E3 plays a role in human retinal photoreceptor differentiation and degeneration . Proceedings of the National Academy of Sciences of the United States of America . 99 . 1 . 473–8 . January 2002 . 11773633 . 117584 . 10.1073/pnas.022533099 . free .
• Sharon D, Sandberg MA, Caruso RC, Berson EL, Dryja TP . Shared mutations in NR2E3 in enhanced S-cone syndrome, Goldmann-Favre syndrome, and many cases of clumped pigmentary retinal degeneration . Archives of Ophthalmology . 121 . 9 . 1316–23 . September 2003 . 12963616 . 10.1001/archopht.121.9.1316 .
• Cheng H, Khanna H, Oh EC, Hicks D, Mitton KP, Swaroop A . Photoreceptor-specific nuclear receptor NR2E3 functions as a transcriptional activator in rod photoreceptors . Human Molecular Genetics . 13 . 15 . 1563–75 . August 2004 . 15190009 . 10.1093/hmg/ddh173 .
• Bumsted O'Brien KM, Cheng H, Jiang Y, Schulte D, Swaroop A, Hendrickson AE . Expression of photoreceptor-specific nuclear receptor NR2E3 in rod photoreceptors of fetal human retina . Investigative Ophthalmology & Visual Science . 45 . 8 . 2807–12 . August 2004 . 15277507 . 10.1167/iovs.03-1317 .
• Wright AF, Reddick AC, Schwartz SB, Ferguson JS, Aleman TS, Kellner U, Jurklies B, Schuster A, Zrenner E, Wissinger B, Lennon A, Shu X, Cideciyan AV, Stone EM, Jacobson SG, Swaroop A . 6 . Mutation analysis of NR2E3 and NRL genes in Enhanced S Cone Syndrome . Human Mutation . 24 . 5 . 439 . November 2004 . 15459973 . 10.1002/humu.9285 . 18561451 .
• Chen J, Rattner A, Nathans J . The rod photoreceptor-specific nuclear receptor Nr2e3 represses transcription of multiple cone-specific genes . The Journal of Neuroscience . 25 . 1 . 118–29 . January 2005 . 15634773 . 6725199 . 10.1523/JNEUROSCI.3571-04.2005 .
• Peng GH, Ahmad O, Ahmad F, Liu J, Chen S . The photoreceptor-specific nuclear receptor Nr2e3 interacts with Crx and exerts opposing effects on the transcription of rod versus cone genes . Human Molecular Genetics . 14 . 6 . 747–64 . March 2005 . 15689355 . 10.1093/hmg/ddi070 . free .
• Hayashi T, Gekka T, Goto-Omoto S, Takeuchi T, Kubo A, Kitahara K . Novel NR2E3 mutations (R104Q, R334G) associated with a mild form of enhanced S-cone syndrome demonstrate compound heterozygosity . Ophthalmology . 112 . 12 . 21152115.e1–2115.e10 . December 2005 . 16225923 . 10.1016/j.ophtha.2005.07.002 .
• Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M . Global, in vivo, and site-specific phosphorylation dynamics in signaling networks . Cell . 127 . 3 . 635–48 . November 2006 . 17081983 . 10.1016/j.cell.2006.09.026 . 7827573 . free .
• Coppieters F, Leroy BP, Beysen D, Hellemans J, De Bosscher K, Haegeman G, Robberecht K, Wuyts W, Coucke PJ, De Baere E . 6 . Recurrent mutation in the first zinc finger of the orphan nuclear receptor NR2E3 causes autosomal dominant retinitis pigmentosa . American Journal of Human Genetics . 81 . 1 . 147–57 . July 2007 . 17564971 . 1950922 . 10.1086/518426 .

Notes and References

1. Kobayashi M, Takezawa S, Hara K, Yu RT, Umesono Y, Agata K, Taniwaki M, Yasuda K, Umesono K . 6 . Identification of a photoreceptor cell-specific nuclear receptor . Proceedings of the National Academy of Sciences of the United States of America . 96 . 9 . 4814–9 . April 1999 . 10220376 . 21774 . 10.1073/pnas.96.9.4814 . 1999PNAS...96.4814K . free .
2. Milam AH, Rose L, Cideciyan AV, Barakat MR, Tang WX, Gupta N, Aleman TS, Wright AF, Stone EM, Sheffield VC, Jacobson SG . 6 . The nuclear receptor NR2E3 plays a role in human retinal photoreceptor differentiation and degeneration . Proceedings of the National Academy of Sciences of the United States of America . 99 . 1 . 473–8 . January 2002 . 11773633 . 117584 . 10.1073/pnas.022533099 . free .
3. Tan MH, Zhou XE, Soon FF, Li X, Li J, Yong EL, Melcher K, Xu HE . 6 . The crystal structure of the orphan nuclear receptor NR2E3/PNR ligand binding domain reveals a dimeric auto-repressed conformation . PLOS ONE . 8 . 9 . e74359 . 2013 . 24069298 . 3771917 . 10.1371/journal.pone.0074359 . free . 2013PLoSO...874359T .
4. Nakamura PA, Tang S, Shimchuk AA, Ding S, Reh TA . Potential of Small Molecule-Mediated Reprogramming of Rod Photoreceptors to Treat Retinitis Pigmentosa . Investigative Ophthalmology & Visual Science . 57 . 14 . 6407–6415 . November 2016 . 27893103 . 5134355 . 10.1167/iovs.16-20177 .
5. Haider NB, Jacobson SG, Cideciyan AV, Swiderski R, Streb LM, Searby C, Beck G, Hockey R, Hanna DB, Gorman S, Duhl D, Carmi R, Bennett J, Weleber RG, Fishman GA, Wright AF, Stone EM, Sheffield VC . 6 . Mutation of a nuclear receptor gene, NR2E3, causes enhanced S cone syndrome, a disorder of retinal cell fate . Nature Genetics . 24 . 2 . 127–31 . February 2000 . 10655056 . 10.1038/72777 . 19508439 .
6. Gerber S, Rozet JM, Takezawa SI, dos Santos LC, Lopes L, Gribouval O, Penet C, Perrault I, Ducroq D, Souied E, Jeanpierre M, Romana S, Frézal J, Ferraz F, Yu-Umesono R, Munnich A, Kaplan J . 6 . The photoreceptor cell-specific nuclear receptor gene (PNR) accounts for retinitis pigmentosa in the Crypto-Jews from Portugal (Marranos), survivors from the Spanish Inquisition . Human Genetics . 107 . 3 . 276–84 . September 2000 . 11071390 . 10.1007/s004390000350 . 10400.17/1708 . 2774255 . free .
7. Chavala SH, Sari A, Lewis H, Pauer GJ, Simpson E, Hagstrom SA, Traboulsi EI . An Arg311Gln NR2E3 mutation in a family with classic Goldmann-Favre syndrome . The British Journal of Ophthalmology . 89 . 8 . 1065–6 . August 2005 . 16024868 . 1772771 . 10.1136/bjo.2005.068130 .