Photoreceptor Cell Development Regulation


Photoreceptors, the specialised cells that signal visual information, evolved ∼600 million years ago, well before the divergence of vertebrates and invertebrates. Metazoan organisms have since evolved variant developmental circuitries that involve specific extrinsic and intrinsic factors to form distinct types of photoreceptor cells. Owing to studies on animal models and human ocular anomalies, the characterisation of several regulatory genes that are essential for mammalian photoreceptor development, namely CRX, NRL and NR2E3, has progressed significantly. These studies have now been further extended by the application of systems level analyses, which have begun to elucidate the underlying gene regulatory network (GRN) for photoreceptor differentiation. Insights from these studies have identified therapeutic targets and have allowed the development of protocols for the derivation of photoreceptors from mammalian embryonic stem (ES) cells and induced pluripotent stem (iPS) cells. Together with the added identification of regulatory roles for microRNAs (ribonucleic acid) and posttranslational modifications, photoreceptor development presents an unprecedented opportunity for developing regenerative medicine‐based therapeutic applications for ocular diseases.

Key Concepts:

  • Photoreceptors are specialised neuronal cells that absorb and signal electromagnetic radiation‐based information, that is photons, via alterations in their membrane potential.

  • Rhabdomeric photoreceptors are predominantly, but not exclusively, found to play a visual sensory role in invertebrates and are characterised by the folding of their apical cell surface into numerous microvilli, which function to store photopigments.

  • Ciliary photoreceptors are predominantly, but not exclusively, found to play a visual sensory role in vertebrates and are characterised by the extensive folding of their ciliary membranes for storage of photopigments.

  • Retinal progenitor cells pass through successive states of ‘developmental competence’, which are orchestrated by a network of temporally expressed intrinsic transcription factors and signalling molecules that regulate the ability of individual cells to differentiate into specific retinal cell types.

  • In early oculogenesis, the Notch receptor functions to repress photoreceptor differentiation in multipotent retinal progenitor cells.

  • Loss of just one transcription factor, Nrl, leads to the complete transformation of rod precursor cells into cone photoreceptor cells in mice.

  • Posttranscriptional events, for example, microRNA‐mediated regulation, are required for achieving appropriate levels of regulatory factors that control photoreceptor differentiation in insects.

  • Posttranslational events, for example, SUMOylation of key regulatory molecules, are essential for achieving activation of rod‐expressed genes and repression of cone‐expressed genes in mammalian rod photoreceptor development.

  • High‐throughput genomic technologies like microarrays, deep‐sequencing and serial analysis of gene expression (SAGE), among others, will lead to a thorough analysis of photoreceptor‐expressed transcripts, which in turn allows for the construction of the underlying gene regulatory networks (GRNs).

  • Information gained from the functional characterisation of signalling molecules, transcription factors and gene regulatory networks that operate in photoreceptor cell development, are essential for the identification of potential therapeutic targets, and can also be applied to direct the differentiation of embryonic stem (ES) cells and induced pluripotent stem (iPS) cells to photoreceptor cell fates.

Keywords: photoreceptor; opsin; retina; gene regulatory network (GRN); stem cells

Figure 1.

Drosophila retinal pattern formation. (a) The movement of the morphogenetic furrow in the imaginal disc initiates photoreceptor cell differentiation in Drosophila. (HH) and (DPP) signalling pathways function co‐operatively to drive this wave of differentiation. Eye pattern formation in the anterior‐dorsal and anterior‐ventral regions is prevented by the action of (WG). (b) Epidermal growth factor (EGF) signalling and atonal expression promote R8 photoreceptor differentiation. Subsequently, a second burst of EGF activity plus rough expression results in R2 and R5 differentiation. Additional EGF signalling events and transcription factors act to sequentially recruit the remaining members of the ommatidium.

Figure 2.

Regulatory factors involved in Drosophila photoreceptor development. An evolutionarily conserved network of transcription factors involving twin of eyeless (Toy), eyeless (Ey), since oculis (So), eyes absent (Eya) and dachshund (Dac) functions along with signalling through the epidermal growth factor receptor (EGFR) and Notch (N) pathways to specify the eye‐antennal imaginal disc. Beginning from the late larval and early pupal stages, photoreceptors start to differentiate into the specific cell types R1–8. The Spalt transcription factor encoding gene sal functions to form a generic colour photoreceptor. Expression of the transcription factor encoding genes pros and sens in individual precursor cells leads to their differentiation into R7 and R8 photoreceptors, respectively. In inner photoreceptors specialised for colour vision, the orthodenticle K50 homeodomain transcription factor encoding gene, otd, directly regulates expression of rhodopsins Rh3 and Rh5 to specify the pale ommatidial fate. Spineless (ss), which encodes a bHLH‐PAS transcription factor, is necessary for generating the yellow ommatidial fate. R7 pale (Rh3‐expressing) or yellow (Rh4‐expressing) ommatidia signal the underlying R8 cell as to its specific fate. This signal is interpreted in the R8 cell through the action of a serine/threonine kinase encoding gene, warts, to form a yellow (Rh6‐expressing) R8 photoreceptor, or through the action of a Pleckstrin homology domain protein‐encoding gene, melted, that is necessary to form a pale (Rh5‐exressing) R8 photoreceptor. Lastly, specialised R7 and R8 photoreceptors in the polarising light receptive region of the retina, termed the Dorsal Rim Area (DRA), are formed because of the action of the hth encoded homeoprotein transcription factor, Homothorax. Reprinted from Morante et al., , with permission from Elsevier.

Figure 3.

Vertebrate retinal development. (a) The laminated cellular structure of the vertebrate retina. A, amacrine cells; B, bipolar cells; C, cones; G, ganglion cells; H, horizontal cells; I, interplexiform cells; M, Müller cells; R, rods and hv, humour vitreus. (b) The time course of cell generation for each retinal cell type in the mouse. Modified and reproduced from Young . Copyright © by Wiley. Reprinted with permission of Wiley‐Liss, Inc. a subsidiary of Wiley.

Figure 4.

Vertebrate photoreceptor cell development takes place as precursor cells proliferate in response to the actions of growth factors and the transcription factors, Chx10, Pax6 and Rx. Environmental factors along with Otx2 and Rb act on progenitor cells that have escaped Notch inhibition to induce differentiation. Some of these cells express Crx, which is a proposed competence factor for photoreceptor cell formation. Crx+ cells which express Nrl are biased to form rod photoreceptors, whereas the ones that retain only Crx expression are fated to become cones. Nr2e3 is turned on by the actions of Crx and Nrl to ensure commitment to rod cell fate. Later, opsin synthesis regulated by the appropriate regulatory factors like Tr2β and Rorβ completes the terminal differentiation of rod and cone cells. It is estimated that the process of differentiation of post‐mitotic photoreceptor precursor cells into mature opsin‐containing rod and cone photoreceptors takes between 5 and 12 days in mice and 4–5 weeks in humans. Modified from Oh et al. . Copyright © by the National Academy of Sciences.

Figure 5.

Gene regulatory network (GRN) for vertebrate photoreceptor cell development. The GRN is constructed from both genetic and biochemical data after careful analysis of the literature. Otx and Crx are situated at the apex of the photoreceptor developmental pathway. Positive input is indicated by arrow, whereas negative inputs is indicated by (⊥). Protein–protein interaction is denoted by (•). Implied function that needs to be proven in vivo is denoted by (?).



Adler R and Raymond PA (2008) Have we achieved a unified model of photoreceptor cell fate specification in vertebrates? Brain Research 1192: 134–150.

Akimoto M, Cheng H, Zhu D et al. (2006) Targeting of GFP to newborn rods by Nrl promoter and temporal expression profiling of flow‐sorted photoreceptors. Proceedings of the National Academy of Sciences of the USA 103: 3890–3895.

Belliveau MJ and Cepko CL (1999) Extrinsic and intrinsic factors control the genesis of amacrine and cone cells in the rat retina. Development 126: 555–566.

Blackshaw S, Fraioli RE, Furukawa T and Cepko CL (2001) Comprehensive analysis of photoreceptor gene expression and the identification of candidate retinal disease genes. Cell 107: 579–589.

Brown NL, Kanekar S, Vetter ML et al. (1998) Math5 encodes a murine basic helix‐loop‐helix transcription factor expressed during early stages of retinal neurogenesis. Development 125: 4821–4833.

Burmeister M, Novak J, Liang MY et al. (1996) Ocular retardation mouse caused by Chx10 homeobox null allele: impaired retinal progenitor proliferation and bipolar cell differentiation. Nature Genetics 12: 376–384.

Cepko CL (2001) Genomics approaches to photoreceptor development and disease. Harvey Lectures 97: 85–110.

Chen B and Cepko CL (2009) HDAC4 regulates neuronal survival in normal and diseased retinas. Science 323: 256–259.

Chen S, Wang QL, Nie Z et al. (1997) Crx, a novel Otx‐like paired‐homeodomain protein, binds to and transactivates photoreceptor cell‐specific genes. Neuron 19: 1017–1030.

Corbo JC and Cepko CL (2005) A hybrid photoreceptor expressing both rod and cone genes in a mouse model of enhanced S‐cone syndrome. PLoS Genetics 1: e11.

Corbo JC, Myers CA, Lawrence KA, Jadhav AP and Cepko CL (2007) A typology of photoreceptor gene expression patterns in the mouse. Proceedings of the National Academy of Sciences of the USA 104: 12069–12074.

Danko CG, McIlvain VA, Qin M, Knox BE and Pertsov AM (2007) Bioinformatic identification of novel putative photoreceptor specific cis‐elements. BMC Bioinformatics 8: 407.

Dorsky RI, Chang WS, Rapaport DH and Harris WA (1997) Regulation of neuronal diversity in the Xenopus retina by Delta signalling. Nature 385: 67–70.

Furukawa T, Morrow EM and Cepko CL (1997) Crx, a novel otx‐like homeobox gene, shows photoreceptor‐specific expression and regulates photoreceptor differentiation. Cell 91: 531–541.

Haider NB, Jacobson SG, Cideciyan AV et al. (2000) Mutation of a nuclear receptor gene, NR2E3, causes enhanced S cone syndrome, a disorder of retinal cell fate. Nature Genetics 24: 127–131.

Hattar S, Liao HW, Takao M, Berson DM and Yau KW (2002) Melanopsin‐containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity. Science 295: 1065–1070.

Hennig AK, Peng GH and Chen S (2008) Regulation of photoreceptor gene expression by Crx‐associated transcription factor network. Brain Research 1192: 114–133.

Hsiau TH, Diaconu C, Myers CA et al. (2007) The cis‐regulatory logic of the mammalian photoreceptor transcriptional network. PLoS ONE 2: e643.

Jadhav AP, Mason HA and Cepko CL (2006) Notch 1 inhibits photoreceptor production in the developing mammalian retina. Development 133: 913–923.

Jarman AP, Grell EH, Ackerman L, Jan LY and Jan YN (1994) Atonal is the proneural gene for Drosophila photoreceptors. Nature 369: 398–400.

Jeon CJ, Strettoi E and Masland RH (1998) The major cell populations of the mouse retina. Journal of Neuroscience 18: 8936–8946.

Jia L, Oh EC, Ng L et al. (2009) Retinoid‐related orphan nuclear receptor RORbeta is an early acting factor in rod photoreceptor development. Proceedings of the National Academy of Sciences of the USA 106: 17534–17539.

Khanna H, Akimoto M, Siffroi‐Fernandez S et al. (2006) Retinoic acid regulates the expression of photoreceptor transcription factor NRL. Journal of Biological Chemistry 281: 27327–27334.

Khanna H, Davis EE, Murga‐Zamalloa CA et al. (2009) A common allele in RPGRIP1L is a modifier of retinal degeneration in ciliopathies. Nature Genetics 41: 739–745.

Lachke SA and Maas RL (2010) Building the developmental oculome: systems biology in vertebrate eye development and disease. WIREs Systems Biology & Medicine. 2: 293–304.

Lamb TD, Collin SP and Pugh EN Jr (2007) Evolution of the vertebrate eye: opsins, photoreceptors, retina and eye cup. Nature Reviews Neuroscience 8: 960–976.

Lamba DA, Gust J and Reh TA (2009) Transplantation of human embryonic stem cell‐derived photoreceptors restores some visual function in Crx‐deficient mice. Cell Stem Cell 4: 73–79.

Lamba DA, Karl MO, Ware CB and Reh TA (2006) Efficient generation of retinal progenitor cells from human embryonic stem cells. Proceedings of the National Academy of Sciences of the USA 103: 12769–12774.

Li X and Carthew RW (2005) A microRNA mediates EGF receptor signaling and promotes photoreceptor differentiation in the Drosophila eye. Cell 123: 1267–1277.

Liu H, Etter P, Hayes S et al. (2008) NeuroD1 regulates expression of thyroid hormone receptor 2 and cone opsins in the developing mouse retina. Journal of Neuroscience 28: 749–756.

Liu Q, Tan G, Levenkova N et al. (2007) The proteome of the mouse photoreceptor sensory cilium complex. Molecular & Cellular Proteomics 6: 1299–1317.

Lyst MJ and Stancheva I (2007) A role for SUMO modification in transcriptional repression and activation. Biochemical Society Transactions 35: 1389–1392.

MacLaren RE, Pearson RA, MacNeil A et al. (2006) Retinal repair by transplantation of photoreceptor precursors. Nature 444: 203–207.

Mali RS, Zhang X, Hoerauf W et al. (2007) FIZ1 is expressed during photoreceptor maturation, and synergizes with NRL and CRX at rod‐specific promoters in vitro. Experimental Eye Research 84: 349–360.

Marquardt T, Ashery‐Padan R, Andrejewski N et al. (2001) Pax6 is required for the multipotent state of retinal progenitor cells. Cell 105: 43–55.

Mathers PH, Grinberg A, Mahon KA and Jamrich M (1997) The Rx homeobox gene is essential for vertebrate eye development. Nature 387: 603–607.

Mears AJ, Kondo M, Swain PK et al. (2001) Nrl is required for rod photoreceptor development. Nature Genetics 29: 447–452.

Morante J, Desplan C and Celik A (2007) Generating patterned arrays of photoreceptors. Current Opinion in Genetics & Development 17: 314–319.

Morrow EM, Furukawa T, Lee JE and Cepko CL (1999) NeuroD regulates multiple functions in the developing neural retina in rodent. Development 126: 23–36.

Ng L, Hurley JB, Dierks B et al. (2001) A thyroid hormone receptor that is required for the development of green cone photoreceptors. Nature Genetics 27: 94–98.

Nishida A, Furukawa A, Koike C et al. (2003) Otx2 homeobox gene controls retinal photoreceptor cell fate and pineal gland development. Nature Neuroscience 6: 1255–1263.

O'Neill EM, Rebay I, Tjian R and Rubin GM (1994) The activities of two Ets‐related transcription factors required for Drosophila eye development are modulated by the Ras/MAPK pathway. Cell 78: 137–147.

Oh EC, Khan N, Novelli E et al. (2007) Transformation of cone precursors to functional rod photoreceptors by bZIP transcription factor NRL. Proceedings of the National Academy of Sciences of the USA 104: 1679–1684.

Onishi A, Peng GH, Hsu C et al. (2009) Pias3‐dependent SUMOylation directs rod photoreceptor development. Neuron 61: 234–246.

Osakada F, Ikeda H, Mandai M et al. (2008) Toward the generation of rod and cone photoreceptors from mouse, monkey and human embryonic stem cells. Nature Biotechnology 26: 215–224.

Osakada F, Jin ZB, Hirami Y et al. (2009) In vitro differentiation of retinal cells from human pluripotent stem cells by small‐molecule induction. Journal of Cell Science 122: 3169–3179.

Peng GH, Ahmad O, Ahmad F, Liu J and Chen S (2005) 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: 747–764.

Punzo C, Kornacker K and Cepko CL (2009) Stimulation of the insulin/mTOR pathway delays cone death in a mouse model of retinitis pigmentosa. Nature Neuroscience 12: 44–52.

Qian J, Esumi N, Chen Y et al. (2005) Identification of regulatory targets of tissue‐specific transcription factors: application to retina‐specific gene regulation. Nucleic Acids Research 33: 3479–3491.

Rapicavoli NA and Blackshaw S (2009) New meaning in the message: noncoding RNAs and their role in retinal development. Developmental Dynamics 238: 2103–2114.

Roberts MR, Srinivas M, Forrest D, Morreale de Escobar G and Reh TA (2006) Making the gradient: thyroid hormone regulates cone opsin expression in the developing mouse retina. Proceedings of the National Academy of Sciences of the USA 103: 6218–6223.

Sicinski P, Donaher JL, Parker SB et al. (1995) Cyclin D1 provides a link between development and oncogenesis in the retina and breast. Cell 82: 621–630.

Silver SJ and Rebay I (2005) Signaling circuitries in development: insights from the retinal determination gene network. Development 132: 3–13.

Tan K, Tegner J and Ravasi T (2008) Integrated approaches to uncovering transcription regulatory networks in mammalian cells. Genomics 91: 219–231.

Tomita K, Ishibashi M, Nakahara K et al. (1996) Mammalian hairy and enhancer of split homolog 1 regulates differentiation of retinal neurons and is essential for eye morphogenesis. Neuron 16: 723–734.

Tomlinson A and Struhl G (2001) Delta/Notch and Boss/Sevenless signals act combinatorially to specify the Drosophila R7 photoreceptor. Molecular Cell 7: 487–495.

Trimarchi JM, Stadler MB and Cepko CL (2008) Individual retinal progenitor cells display extensive heterogeneity of gene expression. PLoS ONE 3: e1588.

Turner DL, Snyder EY and Cepko CL (1990) Lineage‐independent determination of cell type in the embryonic mouse retina. Neuron 4: 833–845.

Wang QL, Chen S, Esumi N et al. (2004) QRX, a novel homeobox gene, modulates photoreceptor gene expression. Human Molecular Genetics 13: 1025–1040.

Watanabe T and Raff MC (1990) Rod photoreceptor development in vitro: intrinsic properties of proliferating neuroepithelial cells change as development proceeds in the rat retina. Neuron 4: 461–467.

Yoshida S, Mears AJ, Friedman JS et al. (2004) Expression profiling of the developing and mature Nrl−/− mouse retina: identification of retinal disease candidates and transcriptional regulatory targets of Nrl. Human Molecular Genetics 13: 1487–1503.

Young RW (1985) Cell differentiation in the retina of the mouse. Anatomical Record 212: 199–205.

Yu J, He S, Friedman JS et al. (2004) Altered expression of genes of the Bmp/Smad and Wnt/calcium signaling pathways in the cone‐only Nrl −/− mouse retina, revealed by gene profiling using custom cDNA microarrays. Journal of Biological Chemistry 279: 42211–42220.

Zaidi FH, Hull JT, Peirson SN et al. (2007) Short‐wavelength light sensitivity of circadian, pupillary, and visual awareness in humans lacking an outer retina. Current Biology 17: 2122–2128.

Further Reading

Blackshaw S, Harpavat S, Trimarchi J et al. (2004) Genomic analysis of mouse retinal development. PLoS Biology 2: E247.

Chalupa LM and Williams RW (eds) (2008) Eye, Retina, and Visual System of the Mouse. Cambridge, MA: MIT Press.

Kolb H, Ripps H and Wu S (eds) (2004) Concepts and Challenges in Retinal Biology. Amsterdam, The Netherlands: Elsevier Science Press.

Kumar JP (2008) The molecular circuitry governing retinal determination. Biochimica et Biophysica Acta 1789: 306–314.

MacLaren RE and Pearson RA (2007) Stem cell therapy and the retina. Eye 21: 1352–1359.

Sernagor E, Eglen S, Harris B and Wong R (eds) (2006) Retinal Development. Cambridge, UK: Cambridge University Press.

Tombran‐Tink J and Barnstable CJ (eds) (2008) Visual Transduction and Non‐visual Light Perception. Totowa, NJ: Humana Press.

Tsonis PA (ed.) (2008) Animal Models in Eye Research. San Diego, CA: Academic Press.

Voas MG and Rebay I (2004) Signal integration during development: insights from the Drosophila eye. Developmental Dynamics 229: 162–175.

Williams DS (ed.) (2004) Photoreceptor Cell Biology and Inherited Retinal Degenerations. Singapore: World Scientific Publishing Company.

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Lachke, Salil A, Zhang, Xin, and Maas, Richard L(Jun 2010) Photoreceptor Cell Development Regulation. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0000833.pub2]