Photoreceptor Cell Development Regulation

Salil A Lachke, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
Xin Zhang, Indiana University School of Medicine, Indianapolis, Indiana, USA
Richard L Maas, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA

Published online: June 2010

DOI: 10.1002/9780470015902.a0000833.pub2

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. Hedgehog (HH) and Decapentaplegic (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 Wingless (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., 2007, 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 (1985). 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 Tr2 and Ror 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. (2007). 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 (?).
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    book 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.
    book Williams DS (ed.) (2004) Photoreceptor Cell Biology and Inherited Retinal Degenerations. Singapore: World Scientific Publishing Company.

Related Sub-Topics:

Sensory Systems | Nervous System Development | Genes, Molecules and Cellular Processes | Development of Vertebrate Nervous System | Development of Invertebrate Nervous System | Cell Differentiation and Stem Cells
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Article Title: Photoreceptor Cell Development Regulation
 
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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. http://www.els.net [doi: 10.1002/9780470015902.a0000833.pub2]