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Photoreceptor Cell Fate Specification in Vertebrates Joseph A © 2015. Published by The Company of Biologists Ltd | Development (2015) 142, 3263-3273 doi:10.1242/dev.127043 REVIEW Photoreceptor cell fate specification in vertebrates Joseph A. Brzezinski1 and Thomas A. Reh2,* ABSTRACT specification of photoreceptor fate (see Glossary, Box 1) remains Photoreceptors – the light-sensitive cells in the vertebrate retina – a fascinating and unresolved problem in developmental biology. have been extremely well-characterized with regards to their Diseases that affect the genesis, survival or function of biochemistry, cell biology and physiology. They therefore provide an photoreceptors are major causes of vision loss (Swaroop et al., excellent model for exploring the factors and mechanisms that drive 2010) (Box 2). With recent increases in the prospect of regenerative neural progenitors into a differentiated cell fate in the nervous system. therapies to reverse vision loss, interest in uncovering the As a result, great progress in understanding the transcriptional mechanisms that govern photoreceptor development has grown. network that controls photoreceptor specification and differentiation In this Review, we first provide an overview of retinal has been made over the last 20 years. This progress has also development. This topic has been discussed in many recent enabled the production of photoreceptors from pluripotent stem reviews (Agathocleous and Harris, 2009; Brzezinski and Reh, cells, thereby aiding the development of regenerative medical 2010; Bassett and Wallace, 2012; Xiang, 2013; Boije et al., 2014; approaches to eye disease. In this Review, we outline the signaling Cepko, 2014) and is covered only briefly here. We then discuss the and transcription factors that drive vertebrate photoreceptor current model of photoreceptor development that has emerged from development and discuss how these function together in gene over 25 years of studies on retinogenesis. This model of regulatory networks to control photoreceptor cell fate specification. photoreceptor fate specification has had practical applications in the field of regenerative medicine; some of the key signaling KEY WORDS: Retina, Photoreceptor, Cell fate specification, molecules identified from developmental studies are now being Fate potential, Multipotent, Competence used to enhance photoreceptor genesis from pluripotent stem cells. Throughout the Review, we highlight gaps in our understanding of Introduction photoreceptor fate specification and we finish by discussing several The retina is the part of the eye that senses light and communicates important questions that remain unresolved. this information to the brain via the optic nerve. The vertebrate retina comprises several major cell types – retinal ganglion output Features of retinal and photoreceptor development neurons, bipolar, horizontal and amacrine interneurons, Müller Photoreceptors are generated from a population of proliferative glia and photoreceptors – each of which carries out specialized progenitors (see Glossary, Box 1) in the retinal neuroepithelium, a functions. The detection of light stimuli is mediated by derivative of the neural tube. Rod and cone photoreceptors, along photoreceptors, which are highly specialized neurons that occupy with all of the other retinal cell types, are generated from what are the outermost layer of the retina (Fig. 1A). Vertebrate known as multipotent progenitors. Cell lineage-tracing studies in photoreceptors have a unique polarized morphology (Fig. 1B) that mice, frogs and fish have shown that these progenitor cells can includes an outer segment filled with photoreceptive pigments divide both symmetrically and asymmetrically, and that their (opsins), a connecting cilium, the inner segment, the nucleus, the terminal division can generate different retinal cell types (Turner axon and the synaptic terminal (Rodieck, 1998; Swaroop et al., and Cepko, 1987; Wetts and Fraser, 1988; Turner et al., 1990). 2010). Normal photoreceptor function depends upon maintaining These lineage studies were widely interpreted to demonstrate that these compartments. There are two basic subtypes of progenitors are not limited to producing a single type of retinal photoreceptors: rods and cones. Rod photoreceptors are highly neuron, i.e. there are no progenitors that are solely restricted to sensitive and function in dim light to mediate night vision; they use producing photoreceptors. However, this is not always the case; it rhodopsin as the light-sensitive photopigment. Cone photoreceptors has been known for many years that teleost fish (e.g. zebrafish and are present as several subtypes, each of which contains one or more goldfish) possess a progenitor that is restricted to producing only rod opsins that are maximally sensitive to a different wavelength of photoreceptors, although this has been considered an adaptation to light; cones thus mediate color perception. maintain light sensitivity and rod density as the retina grows in Rods and cones, like other neurons in the central nervous system, postembryonic stages (Raymond and Rivlin, 1987), and more recent express genes that are required for synapse formation and studies have provided evidence for horizontal- and cone-restricted neurotransmitter release. The process of phototransduction progenitors in fish (Godinho et al., 2007; He et al., 2012; Suzuki requires the expression of many genes that uniquely mark et al., 2013). Together, these studies suggest that many of the photoreceptors. Historically, this distinction has facilitated the specification events leading to the generation of photoreceptors, and discovery of gene regulatory networks that control photoreceptor even their specific subtype, can occur in either proliferative specification (see Glossary, Box 1) and physiology. Understanding progenitor or postmitotic precursor (see Glossary, Box 1) cells. the full cascade of gene regulatory events that control the Experiments that correlate the timing of progenitor cell cycle exit (‘birth’) with cell fate have shown that the different retinal cell types 1Department of Ophthalmology, University of Colorado Denver, Aurora, CO 80045, are formed in a partly overlapping sequence that is largely USA. 2Department of Biological Structure, University of Washington, Seattle, conserved among vertebrates (Sidman, 1961; Young, 1985; WA 98195, USA. Altschuler et al., 1991; Rapaport et al., 2004; Wong and *Author for correspondence ([email protected]) Rapaport, 2009). When integrated with lineage-tracing data, these DEVELOPMENT 3263 REVIEW Development (2015) 142, 3263-3273 doi:10.1242/dev.127043 A Retinal anatomy B Photoreceptor structure C Photoreceptor birthdating in mice OS R C OS CCCC CCCC IS ISIS (approx.) OLM Percent born per day born per day Percent C E11 P0 P8 R NucN CytCyt M NucNNuuc ONL B CytCyt H A Axon Axon SynSyny SynSyn OPL Rod Cone G Fig. 1. Retinal anatomy and photoreceptor birthdating profiles. (A) The vertebrate retina comprises seven major cell types. Light-sensitive rod (R, gray) and cone (C, red) photoreceptors occupy the outermost layer of the retina, with rods outnumbering cones (35-to-1 in mice, 20-to-1 in humans). Photoreceptors synapse with bipolar (B, green) and horizontal (H, blue) interneurons. Signals from bipolar cells are relayed to retinal ganglion cells (G, yellow), the axons of which project to multiple areas of the brain. Amacrine (A, cyan) interneurons are located in the inner retina, and Müller glia (M, purple) cell bodies span the thickness of the retina. (B) Rod and cone photoreceptors exhibit highly polarized structures. Light is captured by opsins located in membrane discs (in rods) or folds (in cones) of the outer segment (OS), a modified primary cilium. The inner segment (IS, green) is a specialized area of cytoplasm (Cyt) starting at the outer limiting membrane (OLM) of the retina. It is a site of concentrated biosynthesis and the resulting products are transported through the narrow connecting cilium (CC, pink) into the OS. Cone inner segments tend to be larger than those of rods. Photoreceptor nuclei (Nuc) are densely packed within the outer nuclear layer (ONL), with cone nuclei (C, red) clustered nearer the OLM compared with rod nuclei (R). Photoreceptors span the ONL and extend their axons to the outer plexiform layer (OPL), where they form synapses (Syn) with horizontal and bipolar interneurons. Cones exhibit large multisynaptic pedicles, whereas rods have a smaller synaptic spherule. (C) Timing of permanent cell cycle exit (‘birthdate’) in the developing mouse retina. Neural birthdates follow a central-to-peripheral gradient, starting at embryonic day (E) 11 and finishing around postnatal day (P) 7. Cones (red) are born embryonically, with production peaking at E14.5 and E15.5 in the central and peripheral areas of the retina, respectively. The considerably more numerous rods (gray) are born at all but the earliest times in retinogenesis, peaking at P0 centrally and between P0 and P2 in the peripheral parts of the retina. The area under the curve represents 100% of the cells born for each type. See Carter- Dawson and LaVail (1979) for quantitative details. birthdating studies indicate that the frequency of each cell type might be intrinsically controlled or rely on signals from surrounding generated by progenitors changes over time. In line with this, the cells. A discussion of the mechanisms that underlie this ‘clock’ of isolation of retinal progenitors from different stages of development neurogenesis, and the epigenetic control of photoreceptor further
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