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Transcriptional regulation of photoreceptor development and homeostasis in the mammalian retina

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.

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Figure 1: Functional circuitry of the retina.
Figure 2: Stages of photoreceptor development.
Figure 3: Photoreceptor genesis and maturation in mice and humans.
Figure 4: Transcriptional dominance model of photoreceptor cell fate determination.
Figure 5: A simplified representation of rod gene-regulatory networks.

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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.

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Supplementary information

Supplementary Table 1

Selected inherited retinal diseases that include photoreceptor dysfunction or degeneration. (PDF 253 kb)

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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.

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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

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