Downloaded from http://cshperspectives.cshlp.org/ on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Photoreceptor Cilia and Retinal Ciliopathies Kinga M. Bujakowska, Qin Liu, and Eric A. Pierce Ocular Genomics Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts 02114 Correspondence: [email protected] Photoreceptors are sensory neurons designed to convert light stimuli into neurological re- sponses. This process, called phototransduction, takes place in the outer segments (OS) of rod and cone photoreceptors. OS are specialized sensory cilia, with analogous structures to those present in other nonmotile cilia. Deficient morphogenesis and/or dysfunction of pho- toreceptor sensory cilia (PSC) caused by mutations in a variety of photoreceptor-specific and common cilia genes can lead to inherited retinal degenerations (IRDs). IRDs can manifest as isolated retinal diseases or syndromic diseases. In this review, we describe the structure and composition of PSC and different forms of ciliopathies with retinal involvement. We review the genetics of the IRDs, which are monogenic disorders but genetically diverse with regard to causality. hotoreceptors are sensory neurons designed morphogenesis and/or dysfunction of photore- Pto convert light stimuli into electrical re- ceptor sensory cilia (PSC) caused by mutations sponses, a process called phototransduction. in a variety of photoreceptor-specific and com- Phototransduction takes place in the highly spe- mon cilia genes can lead to a group of clinical cialized compartment of photoreceptors, the manifestations, called inherited retinal degener- outer segment (OS) (Pearring et al. 2013; Mol- ations (IRDs). In this review, we will discuss the day and Moritz 2015). The OS of the rod and structure and composition of PSC and different cone photoreceptors differ in structure and pro- forms of ciliopathies with retinal involvement. tein composition, related to their functional ad- aptation, in which rods have high sensitivity necessary in dim light and cones are responsible SPECIALIZED PHOTORECEPTOR for the high-resolution color vision working in SENSORY CILIA bright light (Lamb and Pugh 2006; Lamb et al. In vertebrate retina, the visual function depends 2007). Research over the past decade on the on the formation of complex sensory cilia of rod genetic and molecular components of photore- and cone photoreceptors. Photoreceptors are ceptors in vertebrate retinae has led to the clear highly polarized neurons, composed of four recognition that photoreceptor OS are special- distinct compartments: the OS, the inner seg- ized sensory cilia (Liu et al. 2007a; Ramamurthy ment (IS), the nucleus and a short axon extend- and Cayouette 2009; Khanna 2015). Deficient ing to second order neurons (bipolar and hor- Editors: Wallace Marshall and Renata Basto Additional Perspectives on Cilia available at www.cshperspectives.org Copyright # 2017 Cold Spring Harbor Laboratory Press; all rights reserved Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a028274 1 Downloaded from http://cshperspectives.cshlp.org/ on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press K.M. Bujakowska et al. izontal cells) (Fig. 1) (Kennedy and Malicki et al. 2007a; Ramamurthy and Cayouette 2009; 2009; Pearring et al. 2013; Molday and Moritz Khanna 2015). The recognition of PSCs as dis- 2015). OS are ciliary organelles with analogous tinct morphological structures is valuable for structure to the primary sensory cilia in other the study of photoreceptor cell biology and dis- cell types (Rosenbaum and Witman 2002; Liu ease pathogenesis. Studies of genes involved in IRDs and other ciliopathies have identified dozens of novel components of the PSCs. A comprehensive proteomic study of mouse PSCs has identified 2000 proteins in this or- ganelle, out of which hundreds are present in other cilia (Liu et al. 2007a). These findings have greatly improved our understanding of OS how photoreceptor cilia are built and main- tained, and how these processes are disrupted in disease. Ciliary Backbone of PSC The structure of the PSC is analogous to other CP cilia, where the axoneme arises from the basal Ax body through the transition zone (also called the “connecting cilium”) and extends up to two-thirds of the OS (Fig. 1) (De Robertis TZ 1956; Kaplan et al. 1987). The basal body also BB nucleates the ciliary rootlet, which extends into the IS, and which is covalently linked to the PSC IS structure (Yanget al. 2005; Liu et al. 2007a). The RT basal body contains nine triplet microtubules, two of which extend further to form the axo- neme and the third anchors transition fibers linking the basal body to the plasma membrane. The nine doublet microtubules in the transition zone are cross-linked to the surrounding plasma membrane by Y-link structures (Besharse et al. Ncl 1985; Horst et al. 1990). These Y-link structures are absent in the rest of the axoneme. The transition zone of rods and cones measures 0.3 mm in diameter and 1–1.5 mm in length, which is fairly consistent throughout the species Syn (Besharse et al. 1985). This structure was origi- nally called the “connecting cilium” by De Ro- Figure 1. Photoreceptor structure. Schematic repre- bertis in 1956, when he was studying some of the sentation of the rod photoreceptor with sensory first electron micrographs of photoreceptor cells cilia components indicated. The drawings to the (De Robertis 1956). However, as an analogy with left of the photoreceptor represent the cross-section- other primary sensory cilia, we refer to this re- al view of the microtubule structure of the distal axoneme (Ax), proximal Ax, transition zone (TZ), gion as a transition zone. Above the transition and basal body (BB). RT, rootlet; OS, outer seg- zone, disc morphogenesis takes place where the ment; CP, calyceal process; IS, inner segment; Ncl, surrounding plasma membrane transforms into nucleus; Syn, synapse. the disc precursors through membrane evagina- 2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a028274 Downloaded from http://cshperspectives.cshlp.org/ on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press Photoreceptor Cilia and Retinal Ciliopathies tion (Steinberg et al. 1980; Ding et al. 2015; Pugh ber 1 (CDHR1) were associated with the open 2015). At the distal part of the PSC axoneme, the lamellar evaginations in rod and cone discs in double microtubules are reduced to singlets Xenopus laevis and mice, respectively (Rattner (Fig. 1) (Rosenbaum and Witman 2002; Pear- et al. 2001; Han et al. 2012). PSC are responsible ring et al. 2013). for mediating the sensory transduction of the visual system with a number of proteins in- volved in this process, including the above- Other Structural Components of Outer mentioned rhodopsin. Most of these proteins Segments are expressed specifically in PSC and, when PSCs are highly specialized sensory cilia, adapt- mutated, cause nonsyndromic IRDs (Table 1) ed for light detection by the presence of tightly (Dryja et al. 1990; Farrar et al. 1990; Kajiwara packed membranous discs containing visual et al. 1991, 1994; Travis et al. 1991; Bascom et al. pigments and other phototransduction pro- 1992; Rosenfeld et al. 1992; Dryja et al. 1993; teins (Sjostrand 1953; Nickell et al. 2007; Gil- Maw et al. 2000; Yang et al. 2008). Studies of liam et al. 2012). PSCs are among the largest mutant animals have shown that the above- of mammalian cilia (Pan et al. 2005) and, like mentioned proteins are essential for OS disc other cilia, they are comprised of a cytoskeleton morphogenesis and maintenance (Sanyal et al. backbone and a membrane domain, which is 1980; Clarke et al. 2000; Rattner et al. 2001; distinct from the surrounding plasma mem- Dellett et al. 2015). brane (Steinberg et al. 1980; Molday and Mol- day 1987). In murine rods, the numerous mem- PROTEIN TRANSPORT TO PSC branous discs in the PSC compartment are stacked at a density of 30 discs per microme- A unique feature of the photoreceptor OS is the ter, which is thought to be constant throughout high level of its renewal. Each day 10% of the species (Nickell et al. 2007; Gilliam et al. 2012). OS is shed from the distal tip, which is replaced Such OS organization provides a large surface by new disc formation at the base of the PSC area for optimized photon capture and rapid (Young 1967). This necessitates a robust system signal transduction reactions to occur. Rhodop- of protein synthesis in the IS and efficient traf- sin is the most abundant disc membrane pro- ficking of selected proteins to the photorecep- tein, organized as rows of dimers with a density tor OS. of 48,000 monomers per mm2 (Fotiadis et al. 2003). With this high density in the disc mem- Intraflagellar Transport in PSC branes, rhodopsin plays an important structural role apart from being the main visual pigment The axoneme, initiated at the mother centriole, in the retina (Wang and Deretic 2014). The rim is built and maintained by extending its distal of the photoreceptor discs contains two tetra- (þ) end (Pedersen and Rosenbaum 2008). Be- spanins: Rds/peripherin-2 (PRPH2) and reti- cause protein synthesis occurs in the IS, the ax- nal OS membrane protein 1 (ROM1), which oneme building blocks need to be transported facilitate the folding of the OS discs and are to the distal end via intraflagellar transport crucial for rim formation and sorting of the (IFT) (Rosenbaum and Witman 2002; Pedersen OS proteins during the OS biogenesis (Molday and Rosenbaum 2008; Taschneret al. 2012). The et al. 1987; Goldberg and Molday 1996; Arikawa anterograde transport from the base to the tip of et al. 2011). PRPH2 and its homolog ROM1 the axoneme is mediated by IFT complex B both form homodimers and then associate to- (IFT-B), where kinesin-2 is the motor protein gether to form tetrameric complexes, exclusive- (Rosenbaum and Witman 2002).