Key Points
-
Vision begins in the retina at the rod and cone photoreceptors, which are sensory neurons with specialized visual pigments for capturing light quanta. Most mammals have one type of rod and two types of cone (M and S) photoreceptors that confer dichromatic vision. Humans have one type of rod and three cone subtypes that confer trichromacy.
-
All retinal neurons, including photoreceptors, are generated from multipotent progenitor cells through a step-wise process that increasingly restricts lineage choices and commits cells to a particular fate. The balanced actions of six key transcription factors (the paired-type homeodomain transcription factor OTX2, cone–rod homeobox protein CRX, neural retina leucine zipper protein (NRL), photoreceptor-specific nuclear receptor (NR2E3), nuclear receptor RORβ and thyroid hormone receptor β2 (TRβ2)) are crucial as retinal progenitors commit to a rod or cone lineage.
-
We propose a 'transcriptional dominance' model of photoreceptor fate determination that includes three fundamental attributes: that all photoreceptor types originate from a common postmitotic photoreceptor precursor that has the potential to form rods or any cone type; that such precursors differentiate by 'default' as S cones unless additional signals promote acquisition of a rod or M cone identity; and that the particular fate acquired by a precursor results from a contest among specific transcription factors.
-
We predict that transcriptional signals control two key points during fate specification: first, the decision to form a rod or a cone — dictated by NRL and its downstream target NR2E3; second, the decision for a cone to acquire an S cone or M cone identity, largely determined by thyroid hormone receptor TRβ2. OTX2 and RORβ act upstream of NRL, whereas CRX induces both rod and cone genes during photoreceptor maturation.
-
Abnormalities, dysfunction and/or death of photoreceptors constitute the primary cause of visual impairment or blindness in most retinal diseases. Many retinal disease genes are targets of the differentiation factors NRL, CRX and NR2E3, which also maintain rod homeostasis. Studies of transcriptional regulation underlying photoreceptor development should further advance gene- and small-molecule-based interventions and cell-based transplantation therapies for retinal degenerative diseases.
Abstract
In the developing vertebrate retina, diverse neuronal subtypes originate from multipotent progenitors in a conserved order and are integrated into an intricate laminated architecture. Recent progress in mammalian photoreceptor development has identified a complex relationship between six key transcription-regulatory factors (RORβ, OTX2, NRL, CRX, NR2E3 and TRβ2) that determine rod versus M cone or S cone cell fate. We propose a step-wise 'transcriptional dominance' model of photoreceptor cell fate determination, with the S cone representing the default state of a generic photoreceptor precursor. Elucidation of gene-regulatory networks that dictate photoreceptor genesis and homeostasis will have wider implications for understanding the development of nervous system function and for the treatment of neurodegenerative diseases.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Rodieck, R. W. The First Steps in Seeing (Sinauer Associates Publishers, Sunderland, Massachusetts,1998).
Dowling, J. E. The Retina: An Approachable Part of the Brain. (Belknap Press, Harvard Univ. Press, 1987).
Masland, R. H. The fundamental plan of the retina. Nature Neurosci. 4, 877–886 (2001).
Wassle, H. Parallel processing in the mammalian retina. Nature Rev. Neurosci. 5, 747–757 (2004).
Luo, D. G., Xue, T. & Yau, K. W. How vision begins: an odyssey. Proc. Natl Acad. Sci. USA 105, 9855–9862 (2008).
Carter-Dawson, L. D. & LaVail, M. M. Rods and cones in the mouse retina. I. Structural analysis using light and electron microscopy. J. Comp. Neurol. 188, 245–262 (1979).
Roorda, A. & Williams, D. R. The arrangement of the three cone classes in the living human eye. Nature 397, 520–522 (1999).
Xiao, M. & Hendrickson, A. Spatial and temporal expression of short, long/medium, or both opsins in human fetal cones. J. Comp. Neurol. 425, 545–559 (2000).
Galli-Resta, L. Putting neurons in the right places: local interactions in the genesis of retinal architecture. Trends Neurosci. 25, 638–643 (2002).
Curcio, C. A., Sloan, K. R., Kalina, R. E. & Hendrickson, A. E. Human photoreceptor topography. J. Comp. Neurol. 292, 497–523 (1990).
Nathans, J., Thomas, D. & Hogness, D. S. Molecular genetics of human color vision: the genes encoding blue, green, and red pigments. Science 232, 193–202 (1986). Together with another paper in the same issue of Science , Nathans and colleagues establish the fundamental basis for colour vision and associated inherited variations in humans.
Deeb, S. S. Genetics of variation in human color vision and the retinal cone mosaic. Curr. Opin. Genet. Dev. 16, 301–307 (2006).
Szel, A., Rohlich, P., Mieziewska, K., Aguirre, G. & van Veen, T. Spatial and temporal differences between the expression of short- and middle-wave sensitive cone pigments in the mouse retina: a developmental study. J. Comp. Neurol. 331, 564–577 (1993).
Szel, A., Lukats, A., Fekete, T., Szepessy, Z. & Rohlich, P. Photoreceptor distribution in the retinas of subprimate mammals. J. Opt. Soc. Am. A Opt. Image Sci. Vis. 17, 568–579 (2000).
Applebury, M. L. et al. The murine cone photoreceptor: a single cone type expresses both S and M opsins with retinal spatial patterning. Neuron 27, 513–523 (2000).
Nikonov, S. S., Kholodenko, R., Lem, J. & Pugh, E. N. Jr., Physiological features of the S- and M-cone photoreceptors of wild-type mice from single-cell recordings. J. Gen. Physiol. 127, 359–374 (2006).
Adler, R. & Raymond, P. A. Have we achieved a unified model of photoreceptor cell fate specification in vertebrates? Brain Res. 1192, 134–150 (2008).
Livesey, F. J. & Cepko, C. L. Vertebrate neural cell-fate determination: lessons from the retina. Nature Rev. Neurosci. 2, 109–118 (2001).
Marquardt, T. & Gruss, P. Generating neuronal diversity in the retina: one for nearly all. Trends Neurosci. 25, 32–38 (2002).
Carter-Dawson, L. D. & LaVail, M. M. Rods and cones in the mouse retina. II. Autoradiographic analysis of cell generation using tritiated thymidine. J. Comp. Neurol. 188, 263–272 (1979). An elegant delineation of the period of rod and cone photoreceptor genesis in the mouse retina, validated over 25 years later by studies on Nrl and Thrb as specific genetic markers of newly generated rods and cones, respectively.
Young, R. W. Cell differentiation in the retina of the mouse. Anat. Rec. 212, 199–205 (1985).
Holt, C. E., Bertsch, T. W., Ellis, H. M. & Harris, W. A. Cellular determination in the Xenopus retina is independent of lineage and birth date. Neuron 1, 15–26 (1988).
Turner, D. L., Snyder, E. Y. & Cepko, C. L. Lineage-independent determination of cell type in the embryonic mouse retina. Neuron 4, 833–845 (1990).
Rapaport, D. H., Rakic, P. & LaVail, M. M. Spatiotemporal gradients of cell genesis in the primate retina. Perspect. Dev. Neurobiol. 3, 147–159 (1996).
Adler, R. & Hatlee, M. Plasticity and differentiation of embryonic retinal cells after terminal mitosis. Science 243, 391–393 (1989). An early demonstration of developmental plasticity in post-mitotic cells in the chick embryo retina.
Cayouette, M., Poggi, L. & Harris, W. A. Lineage in the vertebrate retina. Trends Neurosci. 29, 563–570 (2006).
Agathocleous, M. & Harris, W. A. From progenitors to differentiated cells in the vertebrate retina. Annu. Rev. Cell Dev. Biol. 25, 45–69 (2009).
Reh, T. A. & Cagan, R. L. Intrinsic and extrinsic signals in the developing vertebrate and fly eyes: viewing vertebrate and invertebrate eyes in the same light. Perspect. Dev. Neurobiol. 2, 183–190 (1994).
Cepko, C. L., Austin, C. P., Yang, X., Alexiades, M. & Ezzeddine, D. Cell fate determination in the vertebrate retina. Proc. Natl Acad. Sci. USA 93, 589–595 (1996). A comprehensive model that helped to integrate the diverse experimental observations on lineage and cell fate determination in the developing retina.
Oliver, G. et al. Six3, a murine homologue of the sine oculis gene, demarcates the most anterior border of the developing neural plate and is expressed during eye development. Development 121, 4045–4055 (1995).
Mathers, P. H., Grinberg, A., Mahon, K. A. & Jamrich, M. The Rx homeobox gene is essential for vertebrate eye development. Nature 387, 603–607 (1997).
Zuber, M. E., Gestri, G., Viczian, A. S., Barsacchi, G. & Harris, W. A. Specification of the vertebrate eye by a network of eye field transcription factors. Development 130, 5155–5167 (2003).
Tetreault, N., Champagne, M. P. & Bernier, G. The LIM homeobox transcription factor Lhx2 is required to specify the retina field and synergistically cooperates with Pax6 for Six6 trans-activation. Dev. Biol. 327, 541–550 (2009).
Livne-Bar, I. et al. Chx10 is required to block photoreceptor differentiation but is dispensable for progenitor proliferation in the postnatal retina. Proc. Natl Acad. Sci. USA 103, 4988–4993 (2006).
Rapaport, D. H., Wong, L. L., Wood, E. D., Yasumura, D. & LaVail, M. M. Timing and topography of cell genesis in the rat retina. J. Comp. Neurol. 474, 304–324 (2004).
Morrow, E. M., Belliveau, M. J. & Cepko, C. L. Two phases of rod photoreceptor differentiation during rat retinal development. J. Neurosci. 18, 3738–3748 (1998).
Cornish, E. E., Hendrickson, A. E. & Provis, J. M. Distribution of short-wavelength-sensitive cones in human fetal and postnatal retina: early development of spatial order and density profiles. Vision Res. 44, 2019–2026 (2004).
Hendrickson, A. et al. Rod photoreceptor differentiation in fetal and infant human retina. Exp. Eye Res. 87, 415–426 (2008).
Yaron, O., Farhy, C., Marquardt, T., Applebury, M. & Ashery-Padan, R. Notch1 functions to suppress cone-photoreceptor fate specification in the developing mouse retina. Development 133, 1367–1378 (2006).
Jadhav, A. P., Mason, H. A. & Cepko, C. L. Notch 1 inhibits photoreceptor production in the developing mammalian retina. Development 133, 913–923 (2006).
Wall, D. S. et al. Progenitor cell proliferation in the retina is dependent on Notch-independent Sonic hedgehog/Hes1 activity. J. Cell Biol. 184, 101–112 (2009).
Hatakeyama, J. & Kageyama, R. Retinal cell fate determination and bHLH factors. Semin. Cell Dev. Biol. 15, 83–89 (2004).
Le, T. T., Wroblewski, E., Patel, S., Riesenberg, A. N. & Brown, N. L. Math5 is required for both early retinal neuron differentiation and cell cycle progression. Dev. Biol. 295, 764–778 (2006).
Nishida, A. et al. Otx2 homeobox gene controls retinal photoreceptor cell fate and pineal gland development. Nature Neurosci. 6, 1255–1263 (2003). This paper puts OTX2 upstream of NRL and CRX in the transcriptional hierarchy controlling photoreceptor differentiation.
Koike, C. et al. Functional roles of Otx2 transcription factor in postnatal mouse retinal development. Mol. Cell. Biol. 27, 8318–8329 (2007).
Chen, S. et al. Crx, a novel Otx-like paired-homeodomain protein, binds to and transactivates photoreceptor cell-specific genes. Neuron 19, 1017–1030 (1997). Refs 46–48 independently identified the homeodomain transcription factor CRX, which plays a key part in photoreceptor development.
Furukawa, T., Morrow, E. M. & Cepko, C. L. Crx, a novel otx-like homeobox gene, shows photoreceptor-specific expression and regulates photoreceptor differentiation. Cell 91, 531–541 (1997).
Freund, C. L. et al. Cone-rod dystrophy due to mutations in a novel photoreceptor-specific homeobox gene (CRX) essential for maintenance of the photoreceptor. Cell 91, 543–553 (1997).
Swaroop, A. et al. Leber congenital amaurosis caused by a homozygous mutation (R90W) in the homeodomain of the retinal transcription factor CRX: direct evidence for the involvement of CRX in the development of photoreceptor function. Hum. Mol. Genet. 8, 299–305 (1999).
Sohocki, M. M. et al. A range of clinical phenotypes associated with mutations in CRX, a photoreceptor transcription-factor gene. Am. J. Hum. Genet. 63, 1307–1315 (1998).
Furukawa, T., Morrow, E. M., Li, T., Davis, F. C. & Cepko, C. L. Retinopathy and attenuated circadian entrainment in Crx-deficient mice. Nature Genet. 23, 466–470 (1999).
Mitton, K. P. et al. The leucine zipper of NRL interacts with the CRX homeodomain. A possible mechanism of transcriptional synergy in rhodopsin regulation. J. Biol. Chem. 275, 29794–29799 (2000).
Hennig, A. K., Peng, G. H. & Chen, S. Regulation of photoreceptor gene expression by Crx-associated transcription factor network. Brain Res. 1192, 114–133 (2008).
Swaroop, A. et al. A conserved retina-specific gene encodes a basic motif/leucine zipper domain. Proc. Natl Acad. Sci. USA 89, 266–270 (1992).
Pittler, S. J. et al. Functional analysis of the rod photoreceptor cGMP phosphodiesterase α-subunit gene promoter: Nrl and Crx are required for full transcriptional activity. J. Biol. Chem. 279, 19800–19807 (2004).
Yoshida, S. et al. Expression profiling of the developing and mature Nrl−/− mouse retina: identification of retinal disease candidates and transcriptional regulatory targets of Nrl. Hum. Mol. Genet. 13, 1487–1503 (2004).
Mears, A. J. et al. Nrl is required for rod photoreceptor development. Nature Genet. 29, 447–452 (2001).
Oh, E. C. et al. Transformation of cone precursors to functional rod photoreceptors by bZIP transcription factor NRL. Proc. Natl Acad. Sci. USA 104, 1679–1684 (2007). Refs 57 and 58 are key papers that demonstrated and established the essential and instructive role of NRL in photoreceptor differentiation.
Kobayashi, M. et al. Identification of a photoreceptor cell-specific nuclear receptor. Proc. Natl Acad. Sci. USA 96, 4814–4819 (1999).
Oh, E. C. et al. Rod differentiation factor NRL activates the expression of nuclear receptor NR2E3 to suppress the development of cone photoreceptors. Brain Res. 1236, 16–29 (2008).
Bumsted O'Brien, K. M. et al. Expression of photoreceptor-specific nuclear receptor NR2E3 in rod photoreceptors of fetal human retina. Invest. Ophthalmol. Vis. Sci. 45, 2807–2812 (2004).
Peng, G. H., 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. Hum. Mol. Genet. 14, 747–764 (2005).
Cheng, H. et al. In vivo function of the orphan nuclear receptor NR2E3 in establishing photoreceptor identity during mammalian retinal development. Hum. Mol. Genet. 15, 2588–2602 (2006).
Chen, J., Rattner, A. & Nathans, J. The rod photoreceptor-specific nuclear receptor Nr2e3 represses transcription of multiple cone-specific genes. J. Neurosci. 25, 118–129 (2005).
Chen, J., Rattner, A. & Nathans, J. Effects of L1 retrotransposon insertion on transcript processing, localization and accumulation: lessons from the retinal degeneration 7 mouse and implications for the genomic ecology of L1 elements. Hum. Mol. Genet. 15, 2146–2156 (2006).
Akhmedov, N. B. et al. A deletion in a photoreceptor-specific nuclear receptor mRNA causes retinal degeneration in the rd7 mouse. Proc. Natl Acad. Sci. USA 97, 5551–5556 (2000).
Corbo, J. C. & Cepko, C. L. A hybrid photoreceptor expressing both rod and cone genes in a mouse model of enhanced S-cone syndrome. PLoS Genet. 1, e11 (2005).
Cheng, H. et al. Photoreceptor-specific nuclear receptor NR2E3 functions as a transcriptional activator in rod photoreceptors. Hum. Mol. Genet. 13, 1563–1575 (2004).
Andre, E. et al. Disruption of retinoid-related orphan receptor β changes circadian behavior, causes retinal degeneration and leads to vacillans phenotype in mice. EMBO J. 17, 3867–3877 (1998).
Chow, L., Levine, E. M. & Reh, T. A. The nuclear receptor transcription factor, retinoid-related orphan receptor β, regulates retinal progenitor proliferation. Mech. Dev. 77, 149–164 (1998).
Jia, L. et al. Retinoid-related orphan nuclear receptor RORβ is an early-acting factor in rod photoreceptor development. Proc. Natl Acad. Sci. USA 106, 17534–17539 (2009). This report refines the transcriptional regulatory networks and places RORβ upstream of NRL in rod differentiation.
Srinivas, M., Ng, L., Liu, H., Jia, L. & Forrest, D. Activation of the blue opsin gene in cone photoreceptor development by retinoid-related orphan receptor β. Mol. Endocrinol. 20, 1728–1741 (2006).
Sjoberg, M., Vennstrom, B. & Forrest, D. Thyroid hormone receptors in chick retinal development: differential expression of mRNAs for α and N-terminal variant β receptors. Development 114, 39–47 (1992).
Ng, L. et al. A thyroid hormone receptor that is required for the development of green cone photoreceptors. Nature Genet. 27, 94–98 (2001). A demonstration that a thyroid hormone receptor, TRβ2, is a key factor in directing differential patterning of M and S opsins in cones in the mammalian retina.
Ng, L., Ma, M., Curran, T. & Forrest, D. Developmental expression of thyroid hormone receptor β2 protein in cone photoreceptors in the mouse. Neuroreport 20, 627–631 (2009).
Lu, A. et al. Retarded developmental expression and patterning of retinal cone opsins in hypothyroid mice. Endocrinology 150, 1536–1544 (2009).
Brzezinski, J., Lamba, D. A. & Reh, T. A. Blimp1 controls photoreceptor versus bipolar cell fate choice during retinal development. Development 137, 619–629 (2010).
Katoh, K. et al. Blimp1 suppresses Chx10 expression in differentiating retinal photoreceptor precursors to ensure proper photoreceptor development. J. Neurosci. 30, 6515–6526 (2010).
Szel, A., van Veen, T. & Rohlich, P. Retinal cone differentiation. Nature 370, 336 (1994).
Akimoto, M. et al. Targeting of GFP to newborn rods by Nrl promoter and temporal expression profiling of flow-sorted photoreceptors. Proc. Natl Acad. Sci. USA 103, 3890–3895 (2006).
Bowmaker, J. K. Evolution of vertebrate visual pigments. Vision Res. 48, 2022–2041 (2008).
Nathans, J. The evolution and physiology of human color vision: insights from molecular genetic studies of visual pigments. Neuron 24, 299–312 (1999).
Mollon, J. D. & Bowmaker, J. K. The spatial arrangement of cones in the primate fovea. Nature 360, 677–679 (1992).
Roberts, M. R., Hendrickson, A., McGuire, C. R. & Reh, T. A. Retinoid X receptor γ is necessary to establish the S-opsin gradient in cone photoreceptors of the developing mouse retina. Invest. Ophthalmol. Vis. Sci. 46, 2897–2904 (2005).
Satoh, S. et al. The spatial patterning of mouse cone opsin expression is regulated by bone morphogenetic protein signaling through downstream effector COUP-TF nuclear receptors. J. Neurosci. 29, 12401–12411 (2009).
Fujieda, H., Bremner, R., Mears, A. J. & Sasaki, H. Retinoic acid receptor-related orphan receptor α regulates a subset of cone genes during mouse retinal development. J. Neurochem. 108, 91–101 (2009).
Jones, I., Ng, L., Liu, H. & Forrest, D. An intron control region differentially regulates expression of thyroid hormone receptor β2 in the cochlea, pituitary, and cone photoreceptors. Mol. Endocrinol. 21, 1108–1119 (2007).
Liu, H. et al. NeuroD1 regulates expression of thyroid hormone receptor 2 and cone opsins in the developing mouse retina. J. Neurosci. 28, 749–756 (2008).
Roberts, M. R., Srinivas, M., Forrest, D., Morreale de Escobar, G. & Reh, T. A. Making the gradient: thyroid hormone regulates cone opsin expression in the developing mouse retina. Proc. Natl Acad. Sci. USA 103, 6218–6223 (2006).
Pessoa, C. N. et al. Thyroid hormone action is required for normal cone opsin expression during mouse retinal development. Invest. Ophthalmol. Vis. Sci. 49, 2039–2045 (2008).
Wang, Y. et al. A locus control region adjacent to the human red and green visual pigment genes. Neuron 9, 429–440 (1992). The first identification of a locus control region that helps determine the selective expression of red-sensitive and green-sensitive photopigment in a specific cone photoreceptor.
Smallwood, P. M., Wang, Y. & Nathans, J. Role of a locus control region in the mutually exclusive expression of human red and green cone pigment genes. Proc. Natl Acad. Sci. USA 99, 1008–1011 (2002).
Wang, Y. et al. Mutually exclusive expression of human red and green visual pigment-reporter transgenes occurs at high frequency in murine cone photoreceptors. Proc. Natl Acad. Sci. USA 96, 5251–5256 (1999).
Deeb, S. S., Liu, Y. & Hayashi, T. Mutually exclusive expression of the L and M pigment genes in the human retinoblastoma cell line WERI: resetting by cell division. Vis. Neurosci. 23, 371–378 (2006).
Tsujimura, T., Chinen, A. & Kawamura, S. Identification of a locus control region for quadruplicated green-sensitive opsin genes in zebrafish. Proc. Natl Acad. Sci. USA 104, 12813–12818 (2007).
Xu, X. L. et al. Retinoblastoma has properties of a cone precursor tumor and depends upon cone-specific MDM2 signaling. Cell 137, 1018–1031 (2009).
Young, R. W. Cell death during differentiation of the retina in the mouse. J. Comp. Neurol. 229, 362–373 (1984).
Voyvodic, J. T., Burne, J. F. & Raff, M. C. Quantification of normal cell death in the rat retina: implications for clone composition in cell lineage analysis. Eur. J. Neurosci. 7, 2469–2478 (1995).
Malicki, J. Cell fate decisions and patterning in the vertebrate retina: the importance of timing, asymmetry, polarity and waves. Curr. Opin. Neurobiol. 14, 15–21 (2004).
Hayashi, T. & Carthew, R. W. Surface mechanics mediate pattern formation in the developing retina. Nature 431, 647–652 (2004).
Stehlin, C. et al. X-ray structure of the orphan nuclear receptor RORβ ligand-binding domain in the active conformation. EMBO J. 20, 5822–5831 (2001).
Yu, R. T. et al. The orphan nuclear receptor Tlx regulates Pax2 and is essential for vision. Proc. Natl Acad. Sci. USA 97, 2621–2625 (2000).
Zhang, C. L., Zou, Y., Yu, R. T., Gage, F. H. & Evans, R. M. Nuclear receptor TLX prevents retinal dystrophy and recruits the corepressor atrophin1. Genes Dev. 20, 1308–1320 (2006).
Young, T. L. & Cepko, C. L. A role for ligand-gated ion channels in rod photoreceptor development. Neuron 41, 867–879 (2004).
Davis, A. A., Matzuk, M. M. & Reh, T. A. Activin A promotes progenitor differentiation into photoreceptors in rodent retina. Mol. Cell. Neurosci. 15, 11–21 (2000).
Levine, E. M., Roelink, H., Turner, J. & Reh, T. A. Sonic hedgehog promotes rod photoreceptor differentiation in mammalian retinal cells in vitro. J. Neurosci. 17, 6277–6288 (1997).
McFarlane, S., Zuber, M. E. & Holt, C. E. A role for the fibroblast growth factor receptor in cell fate decisions in the developing vertebrate retina. Development 125, 3967–3975 (1998).
Zhang, J. et al. Rb regulates proliferation and rod photoreceptor development in the mouse retina. Nature Genet. 36, 351–360 (2004).
Chen, D. et al. Cell-specific effects of RB or RB/p107 loss on retinal development implicate an intrinsically death-resistant cell-of-origin in retinoblastoma. Cancer Cell 5, 539–551 (2004).
Siffroi-Fernandez, S., Felder-Schmittbuhl, M. P., Khanna, H., Swaroop, A. & Hicks, D. FGF19 exhibits neuroprotective effects on adult mammalian photoreceptors in vitro. Invest. Ophthalmol. Vis. Sci. 49, 1696–1704 (2008).
Hyatt, G. A., Schmitt, E. A., Fadool, J. M. & Dowling, J. E. Retinoic acid alters photoreceptor development in vivo. Proc. Natl Acad. Sci. USA 93, 13298–13303 (1996).
Kelley, M. W., Williams, R. C., Turner, J. K., Creech-Kraft, J. M. & Reh, T. A. Retinoic acid promotes rod photoreceptor differentiation in rat retina in vivo. Neuroreport 10, 2389–2394 (1999).
Khanna, H. et al. Retinoic acid regulates the expression of photoreceptor transcription factor NRL. J. Biol. Chem. 281, 27327–27334 (2006).
Rhee, K. D., Goureau, O., Chen, S. & Yang, X. J. Cytokine-induced activation of signal transducer and activator of transcription in photoreceptor precursors regulates rod differentiation in the developing mouse retina. J. Neurosci. 24, 9779–9788 (2004).
Graham, D. R., Overbeek, P. A. & Ash, J. D. Leukemia inhibitory factor blocks expression of Crx and Nrl transcription factors to inhibit photoreceptor differentiation. Invest. Ophthalmol. Vis. Sci. 46, 2601–2610 (2005).
Ezzeddine, Z. D., Yang, X., DeChiara, T., Yancopoulos, G. & Cepko, C. L. Postmitotic cells fated to become rod photoreceptors can be respecified by CNTF treatment of the retina. Development 124, 1055–1067 (1997).
LaVail, M. M. et al. Protection of mouse photoreceptors by survival factors in retinal degenerations. Invest. Ophthalmol. Vis. Sci. 39, 592–602 (1998).
Davidson, E. H. & Levine, M. S. Properties of developmental gene regulatory networks. Proc. Natl Acad. Sci. USA 105, 20063–20066 (2008).
Levine, M. & Davidson, E. H. Gene regulatory networks for development. Proc. Natl Acad. Sci. USA 102, 4936–4942 (2005).
Hsiau, T. H. et al. The cis-regulatory logic of the mammalian photoreceptor transcriptional network. PLoS ONE 2, e643 (2007).
Qian, J. et al. Identification of regulatory targets of tissue-specific transcription factors: application to retina-specific gene regulation. Nucleic Acids Res. 33, 3479–3491 (2005).
Matsuda, T. & Cepko, C. L. Controlled expression of transgenes introduced by in vivo electroporation. Proc. Natl Acad. Sci. USA 104, 1027–1032 (2007).
Friedman, J. S. et al. The minimal transactivation domain of the basic motif-leucine zipper transcription factor NRL interacts with TATA-binding protein. J. Biol. Chem. 279, 47233–47241 (2004).
Swain, P. K. et al. Multiple phosphorylated isoforms of NRL are expressed in rod photoreceptors. J. Biol. Chem. 276, 36824–36830 (2001).
Roger, J. E., Nellissery, J., Kim, D. S. & Swaroop, A. Sumoylation of bZIP transcription factor NRL modulates target gene expression during photoreceptor differentiation. J. Biol. Chem. 15 Jun 2010 (doi:10.1074/jbc.M110.142810).
Kanda, A., Friedman, J. S., Nishiguchi, K. M. & Swaroop, A. Retinopathy mutations in the bZIP protein NRL alter phosphorylation and transcriptional activity. Hum. Mutat. 28, 589–598 (2007).
Onishi, A. et al. Pias3-dependent SUMOylation directs rod photoreceptor development. Neuron 61, 234–246 (2009).
Wright, A. F., Chakarova, C. F., Abd El-Aziz, M. M. & Bhattacharya, S. S. Photoreceptor degeneration: genetic and mechanistic dissection of a complex trait. Nature Rev. Genet. 11, 273–284 (2010).
Hitchcock, P. F. & Raymond, P. A. The teleost retina as a model for developmental and regeneration biology. Zebrafish 1, 257–271 (2004).
Vergara, M. N. & Del Rio-Tsonis, K. Retinal regeneration in the Xenopus laevis tadpole: a new model system. Mol. Vis. 15, 1000–1013 (2009).
Nishiguchi, K. M. et al. Recessive NRL mutations in patients with clumped pigmentary retinal degeneration and relative preservation of blue cone function. Proc. Natl Acad. Sci. USA 101, 17819–17824 (2004).
Haider, N. B. et al. Mutation of a nuclear receptor gene, NR2E3, causes enhanced S cone syndrome, a disorder of retinal cell fate. Nature Genet. 24, 127–131 (2000). An important paper that identified NR2E3 as the gene responsible for enhanced S cone phenotype in humans.
Wright, A. F. et al. Mutation analysis of NR2E3 and NRL genes in enhanced S cone syndrome. Hum. Mutat. 24, 439 (2004).
Jacobson, S. G. et al. Nuclear receptor NR2E3 gene mutations distort human retinal laminar architecture and cause an unusual degeneration. Hum. Mol. Genet. 13, 1893–1902 (2004).
Sharon, D., Sandberg, M. A., Caruso, R. C., Berson, E. L. & Dryja, T. P. Shared mutations in NR2E3 in enhanced S-cone syndrome, Goldmann-Favre syndrome, and many cases of clumped pigmentary retinal degeneration. Arch. Ophthalmol. 121, 1316–1323 (2003).
Kanda, A. & Swaroop, A. A comprehensive analysis of sequence variants and putative disease-causing mutations in photoreceptor-specific nuclear receptor NR2E3. Mol. Vis. 15, 2174–2184 (2009).
Jacobson, S. G. et al. Retinal degenerations with truncation mutations in the cone-rod homeobox (CRX) gene. Invest. Ophthalmol. Vis. Sci. 39, 2417–2426 (1998).
Corbo, J. C., Myers, C. A., Lawrence, K. A., Jadhav, A. P. & Cepko, C. L. A typology of photoreceptor gene expression patterns in the mouse. Proc. Natl Acad. Sci. USA 104, 12069–12074 (2007).
Tucker, T., Marra, M. & Friedman, J. M. Massively parallel sequencing: the next big thing in genetic medicine. Am. J. Hum. Genet. 85, 142–154 (2009).
Ng, S. B. et al. Exome sequencing identifies the cause of a mendelian disorder. Nature Genet. 42, 30–35 (2010).
Barnhill, A. E. et al. Characterization of the retinal proteome during rod photoreceptor genesis. BMC Res. Notes 3, 25 (2010).
Wolkenberg, S. E. et al. Identification of potent agonists of photoreceptor-specific nuclear receptor (NR2E3) and preparation of a radioligand. Bioorg. Med. Chem. Lett. 16, 5001–5004 (2006).
MacLaren, R. E. et al. Retinal repair by transplantation of photoreceptor precursors. Nature 444, 203–207 (2006). This report used NRL-positive rod photoreceptor precursors to show the feasibility and challenges of cell-based replacement therapies for retinal degenerative diseases.
Meyer, J. S. et al. Modeling early retinal development with human embryonic and induced pluripotent stem cells. Proc. Natl Acad. Sci. USA 106, 16698–16703 (2009).
Lamba, D. A., Gust, J. & Reh, T. A. Transplantation of human embryonic stem cell-derived photoreceptors restores some visual function in Crx-deficient mice. Cell Stem Cell 4, 73–79 (2009).
Osakada, F. et al. Toward the generation of rod and cone photoreceptors from mouse, monkey and human embryonic stem cells. Nature Biotech. 26, 215–224 (2008).
Koso, H. et al. CD73, a novel cell surface antigen that characterizes retinal photoreceptor precursor cells. Invest. Ophthalmol. Vis. Sci. 50, 5411–5418 (2009).
Alvarez-Delfin, K. et al. Tbx2b is required for ultraviolet photoreceptor cell specification during zebrafish retinal development. Proc. Natl Acad. Sci. USA 106, 2023–2028 (2009).
Parapuram, S. & Swaroop, A. Eye, Retina, and Visual System of the Mouse (eds Chalupa, L. M. & Williams, R. W.) 675–683 (MIT Press, Cambridge, Massachusetts; London, UK 2008).
Yu, J. et al. From disease genes to cellular pathways: a progress report. Novartis Found. Symp. 255, 147–160; discussion 160–144, 177–148 (2004).
Hansen, R. M. & Fulton, A. B. The course of maturation of rod-mediated visual thresholds in infants. Invest. Ophthalmol. Vis. Sci. 40, 1883–1886 (1999).
Hansen, R. M. & Fulton, A. B. Development of the cone ERG in infants. Invest. Ophthalmol. Vis. Sci. 46, 3458–3462 (2005).
Lerner, L. E., Gribanova, Y. E., Ji, M., Knox, B. E. & Farber, D. B. Nrl and Sp nuclear proteins mediate transcription of rod-specific cGMP-phosphodiesterase β-subunit gene: involvement of multiple response elements. J. Biol. Chem. 276, 34999–35007 (2001).
Acknowledgements
This Review is dedicated to the memory of R. Adler, an outstanding scientist and a generous mentor and colleague. We are grateful to P. Raymond for constructive suggestions, T. Cogliati for productive discussions, and L. Ng, D. Sharlin, Alok Swaroop, S. Veleri and L. Kibiuk for help with the figures. We apologize to colleagues whose papers have not been cited because of page limitations. Our research is supported by intramural programmes of the National Eye Institute and National Institute of Diabetes, Digestive and Kidney Diseases.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Table 1
Selected inherited retinal diseases that include photoreceptor dysfunction or degeneration. (PDF 253 kb)
Related links
Related links
DATABASES
OMIM
FURTHER INFORMATION
Glossary
- Leber's congenital amaurosis
-
A congenital form of early-onset blindness caused by mutations at many genetic loci.
- Retinitis pigmentosa
-
An inherited progressive degeneration of photoreceptors, generally beginning in the peripheral retina with rod cell dysfunction.
- Macular degeneration
-
A progressive dystrophy initially affecting photoreceptors in the 5–6 mm area around the fovea (the macula), which contains a higher ratio of cones to rods than the peripheral retina. Juvenile forms exhibit a Mendelian inheritance pattern, whereas age-related macular degeneration is a complex multifactorial disease.
- Syndromic
-
Related to a pathology or disease involving multiple organs.
- Retinal pigment epithelium
-
A polarized sheet of epithelial cells between the choroidal capillaries and the photoreceptor cells.
- Retinal progenitor cell
-
A proliferating cell that can give rise to mature retinal cells.
- Lineage tracing
-
An experimental method to identify the origin (progenitor) of a differentiated cell.
- Competence
-
The ability of a retinal progenitor or precursor cell to produce specific cell types.
- bHLH transcription factors
-
A family of transcription factors that contain a characteristic basic region and a helix–loop–helix domain.
- Homeodomain transcription factors
-
A family of transcription factors that contain a characteristic DNA recognition domain, called the homeodomain. They are often involved in patterning spatial domains of developing tissues.
- Specification
-
The developmental process that biases an immature cell to adopt a particular fate; the specified cell is not yet committed to the fate and retains developmental plasticity.
- Final mitosis
-
The last mitotic division of a cell.
- Photoreceptor precursor
-
A post-mitotic cell that is not yet differentiated and does not have a mature functional phenotype of a rod or a cone.
- Paired-type homeodomain transcription factor
-
A DNA-binding transcription-regulating protein that contains a homeodomain with the characteristic amino acid residues of the homeodomain of the Drosophila melanogaster Paired transcription factor.
- Basic motif–leucine zipper transcription factor
-
A transcription factor that contains a characteristic basic motif for DNA binding and a leucine zipper domain for dimerization.
- Nuclear receptor
-
A ligand-regulated transcription factor that includes members with known ligands such as thyroid hormone receptor and retinoid X receptor, and those lacking a known physiological ligand such as retinoid-related orphan receptor.
- Superior retina
-
The dorsal region of the light-sensing tissue at the back of the eye.
- Cis-acting elements
-
DNA sequences that affect the transcription of a gene and are present nearby, on the same chromosome.
- Chromatin immunoprecipitation
-
Often abbreviated as ChIP, this is an experimental technique used to identify DNA sequences that bind to a specific DNA-binding protein in vivo.
- Enhanced S cone syndrome
-
An inherited autosomal recessive retinal disease associated with greater sensitivity to blue light, night blindness and eventual photoreceptor degeneration.
Rights and permissions
About this article
Cite this article
Swaroop, A., Kim, D. & Forrest, D. Transcriptional regulation of photoreceptor development and homeostasis in the mammalian retina. Nat Rev Neurosci 11, 563–576 (2010). https://doi.org/10.1038/nrn2880
Issue Date:
DOI: https://doi.org/10.1038/nrn2880
This article is cited by
-
Environmental plasticity in opsin expression due to light and thyroid hormone in adult and developing Astatotilapia burtoni
Hydrobiologia (2023)
-
A second locus contributing to the differential expression of the blue sensitive opsin SWS2A in Lake Malawi cichlids
Hydrobiologia (2023)
-
Role of short-wave-sensitive 1 (sws1) in cone development and first feeding in larval zebrafish
Fish Physiology and Biochemistry (2023)
-
Polyglutamine-expanded ATXN7 alters a specific epigenetic signature underlying photoreceptor identity gene expression in SCA7 mouse retinopathy
Journal of Biomedical Science (2022)
-
Interaction of human CRX and NRL in live HEK293T cells measured using fluorescence resonance energy transfer (FRET)
Scientific Reports (2022)