Transcriptional regulation of photoreceptor development and homeostasis in the mammalian retina

• Published in: Nature reviews. Neuroscience Vol. 11; no. 8; pp. 563 - 576
• Main Authors: Swaroop, Anand, Kim, Douglas, Forrest, Douglas
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2010; Nature Publishing Group
• Subjects: 631/136/142; 631/208/200; 631/378/2571; 692/698/1688/512/2613/1786; Animal Genetics and Genomics; Animals; Apoptosis - genetics; Behavioral Sciences; Biological and medical sciences; Biological Techniques; Biomedical and Life Sciences; Biomedicine; Congenital diseases; Eye and associated structures. Visual pathways and centers. Vision; Fundamental and applied biological sciences. Psychology; General aspects. Models. Methods; Genetic aspects; Growth; Homeostasis; Homeostasis - genetics; Humans; Macular degeneration; Mammals; Nervous system; Neurobiology; Neurodegeneration; Neurogenesis - genetics; Neurosciences; Photoreceptor Cells - physiology; Photoreceptors; Physiological aspects; Retina; Retina - cytology; Retina - growth & development; Retina - physiology; Retinal Diseases - genetics; Retinal Diseases - pathology; Retinal Diseases - physiopathology; review-article; Transcription, Genetic; Vertebrates: nervous system and sense organs; United States; United States > US; Maryland; Rod; Photoreceptor; Homeostasis; Retina; Nervous system; Review; Precursor; Eye; Visual system; Treatment; Models; Transcription factor; Subtype
• ISSN: 1471-003X; 1471-0048; 1471-0048; 1469-3178
• DOI: 10.1038/nrn2880

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. All retinal neurons are generated from multipotent progenitor cells through a step-wise process that increasingly restricts lineage choices. Swaroop and colleagues discuss our current understanding of the transcription factors and gene-regulatory networks involved in photoreceptor subtype specification and photoreceptor development. 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.