This table depicts selected diseases classified as cilia dependent retinopathies, including non-syndromic as well as syndromic forms. Notably, retinal degeneration is a commonly occurring phenotype in all these disorders.
1. Introduction
The primary cilium is a microtubule-based extension of the plasma membrane, which is present in almost all cell types. Ciliary microtubules extend from a basal body (or mother centriole), which docks at the apical membrane. Elegant studies have been carried out to determine the mechanism that regulates the docking of the mother centriole at the membrane for cilia formation. Cilia function as antennae of the cell to detect chemical and physical changes of the microenvironment [1-5]. Owing to their near-ubiquitous nature, cilia are involved in diverse cellular functions, such as patterning of left-right asymmetry (nodal cilia), limb development, bone morphogenesis, and neurosensory functions (mechanosensation, olfaction, and photoreception). Cilia are also implicated in several developmental cascades, such as Wnt signaling, sonic hedgehog signaling, and platelet derived growth factor receptor signaling pathways. Such functions of cilia are brought about by the ability of the ciliary membrane to concentrate a specific subset of membrane proteins in the ciliary compartment as compared to the rest of the cell membrane [6-8].
Cilia are generated by an elaborate process of formation of multiple protein complexes and molecular motor dependent transport of membrane cargo from the proximal to the distal tip, thereby extending the microtubule-based axoneme and the ciliary membrane. Such transport, called Intraflagellar Transport, was initially identified in green alga
2. Photoreceptor sensory cilium and its components
In photoreceptors (rods and cones), cilia are highly specialized and modified into a very distinct part of the cell, which consists multiple membranous discs and initiates phototransduction cascade in response to light. The details of the phototransduction cascade in photoreceptors have been elegantly described elsewhere and will not be covered in this chapter.
There are three major compartments that compose the sensory cilia of photoreceptor: the outer segment (OS), transition zone (TZ) and basal body (Figure 1). Like other primary cilia, photoreceptor cilia are 9+0 microtubule-based structures that are nucleated from the basal body. The mother centriole consists of triplet microtubules and recruits proteins and initiates axoneme assembly. The region adjacent to the basal body is TZ (also called connecting cilium; CC), and consists of doublet microtubules [19-20]. These microtubules are linked to the plasma membrane via transition fibers and Y-linkers, the two distinct structures of TZ [21]. TZ, is a narrow conduit between OS and IS [22]. It is estimated to be 200~500 nm long and 170 nm in diameter. TZ carries out critical transport function by acting as a gate between the IS and the OS. The sensory OS of photoreceptors is enriched in membrane proteins, such as rhodopsin, the cyclic nucleotide gated (CNG) channel, membrane guanylyl cyclases, and peripherin-2 [22-25]. Moreover, the TZ is the only link between the two segments and all proteins need to be transported via this narrow bridge-like structure to the OS. Hence, the TZ serves as a bottleneck as well as a track to generate and maintain the sensory cilium. Several proteins, most of which are associated with human retinal degenerative diseases, are enriched at the TZ of photoreceptors. These include RPGR (retinitis pigmentosa GTPase regulator), CEP290, and Nephrocystin-1 (NPHP1). The microtubules then extend in the form of axoneme. Depending upon the species and cell-type examined, the axoneme can extend to half or full length of the OS. The axoneme is recognized by the fact that it consists of singlet microtubules. Not much is known about the specific function of the axoneme. However, functional analysis of RP1 (retinitis pigmentosa 1) protein that localizes specifically to the axoneme of photoreceptors indicated that it might be involved in stabilizing the OS discs. The membranous discs arranged in a perpendicular orientation to the axoneme and axoneme is believed to prove a structural support to the OS discs.
In addition to maintaining a specific composition of the OS, the photoreceptors also undergo massive protein trafficking. In fact, photoreceptors are most active neurons in the human body and have high-energy demands. This is due to the fact that photoreceptors shed their distal discs at a high rate. It is estimated that 10% of the distal tips of the OS is shed every day by undergoing phagocytosis by the overlying retinal pigmented epithelium (RPE) cells [26]. As no protein synthesis occurs in the OS, all components necessary for the renewal of OS discs are synthesized in the IS and transported to the OS at a very high rate. Approximately 2000 opsins transported to the OS per second in a normal human photoreceptor. Even slight disturbances in the synthesis and transport of proteins to the OS results in photoreceptor degeneration and blindness.
3. Docking of cargo and selection at the TZ of photoreceptors
Even though the OS proteins can be targeted to the cilia, they are first docked at the basal body or adjacent membrane. Multiple models have been proposed for the site of docking of the cargo vesicles [27]. These propose docking directly at the basal body, docking at the lateral plasma membrane and then movement of vesicles in the plasma membrane towards to the ciliary compartment, or docking at a privileged domain of the apical plasma membrane. In vertebrate photoreceptors, such a privileged domain was identified as periciliary ridge. Opsin-laden vesicles were identified at this privileged region as well as transiently in the TZ or CC of photoreceptors [25]. More recently, several ciliary disease proteins mutated in Usher Syndrome, were identified at the periciliary ridge and are thought to make a connecting link between the apical plasma membrane and the ciliary membrane [28-29]. If such a domain plays a direct role in cargo docking awaits further investigations, specifically geared towards ascertaining the composition of this microdomain.
After gaining access to the periciliary ridge, the cargo is transported into the TZ, which acts as a ‘check post’. Due to its elegant meshwork-like structure with Y-shaped linkers that connect the axonemal microtubules to the plasma membrane, its composition of this structure has been the subject of many recent studies. Remarkable studies identified a network of multiprotein complexes of ciliary disease proteins that are found at the TZ and act as diffusion barrier to limit the trafficking of membrane cargo into the ciliary compartment [22, 30-33]. These proteins include RPGR, RPGR-interacting protein 1 (RPGRIP1) [34-35], CEP290/NPHP6 [36-37], MKS-associated proteins and other JBTS and NPHP-associated proteins [6, 38]. Interestingly, these proteins exist in discrete multiprotein complexes at the TZ. A direct role of TZ proteins in acting as a barrier was established when Witman and colleagues showed that mutation in
4. Ciliary disorders of retina (retinal ciliopathies)
As the OS of photoreceptors is a sensory cilium, the degenerative diseases that affect the formation or function of the OS can be categorized as a ciliary disorder. However, for simplicity, we will discuss only those cilia-dependent retinopathies that occur due to defects in ciliary TZ proteins and result in defective trafficking of proteins to the OS. Inactivation of the IFT in conditional
4.1. Non-syndromic retinal ciliopathies
Some forms of RP are caused by defects in genes that encode for ciliary proteins. These include RPGR, RP1, RP2, and TOPORS [50, 56-60]. RP1 and TOPORS are two ciliary proteins mutated in adRP. However, they localize to distinct ciliary compartments: RP1 localizes to the axoneme whereas TOPORS is concentrated in the basal body and transition zone of photoreceptors (Figure 2). The RPGR and RP2 genes are mutated in X-linked forms of RP and together account for more than 90% of XLRP cases [61-64]. Among these, RPGR mutations are found in 70-80% of XLRP and more than 25% of simplex RP males with no family history. On the other hand, RP2 mutations account for 6-10% of XLRP cases. There is considerable clinical heterogeneity among cases of XLRP, which has affected the ability to differentiate between RPGR and RP2 patients in the clinic. This has prompted investigations into genotype-phenotype correlation studies. Such studies are relatively well documented for RPGR patients owing to their majority occurrence as compared to RP2 mutations [65-67]. Nonetheless, recently, a comprehensive analysis of a large group of RP2 patients revealed interesting observations: a majority of RP2 patients seem to exhibit an early involvement of the macula (the central region of the retina) [68].
In cell culture studies, CEP290 has been shown to regulate cilia assembly program by modulating the localization of RAB8A and Pericentriolar Material 1 (PCM1) [85-86]. Additionally, studies using
In addition to the above-mentioned syndromic ciliopathies, there are several other disorders that have been elegantly described elsewhere and are not discussed in this chapter. All these disorders result from defective ciliary development or function. As cilia are involved in regulating numerous signaling cascades, including Wnt signaling, planar cell polarity, hedgehog signaling and cell cycle control, defects in these pathways have also been implicated as a cause of associated disorders. The involvement of signaling cascades in photoreceptor ciliary development and function is not completely understood.
5. Conclusion
As a number of retinal ciliopathy proteins have now been identified the TZ of photoreceptors, the next step is now to delineate the mechanism by which these proteins modulate the function of the TZ and regulate photoreceptor OS development and function. The existence of discrete multiprotein complexes at the TZ indicates that these complexes are involved in the selection and trafficking of specific cargo moieties to the OS. Mutations in the constituent proteins may impair the function of some of the complexes and trafficking of cognate cargo while other complexes may function normally to extend the life of the photoreceptor. However, if the ciliary protein mutated in disease were involved in the trafficking of proteins regulating the development of OS discs, such as rhodopsin, one would expect a severe and early onset retinal degeneration. It has been shown that RPGR, NPHP proteins and BBS proteins (BBSome) exist in multiprotein complexes and regulate ciliary trafficking.
Some of the TZ proteins possess enzymatic activity. As discussed above, RPGR is a GEF for RAB8A while RP2 is a GAP for ARL3. Such activity of these proteins may impart specificity to the cargo vesicle docking and fusion to the ciliary membrane for crossing the TZ barrier. Moreover, modulating the activity of these proteins may provide insights into developing therapeutic paradigms for associated disorders. It should however, be noted that some TZ proteins are also present in other subcellular compartments of the cell. For example, some RPGR isoforms are detected in the basal body and Golgi; RP2 localizes to Golgi and CEP290 localizes to the cytosol and basal body, in addition to the TZ. These observations beg the question: Are these proteins also involved in extraciliary functions or are these proteins participate in alternative pathways to ultimately regulate cilia dependent cascades. It was recently shown that CEP290 interacts with RKIP, which is involved in modulating MAP Kinase signaling cascades. In addition, CEP290 modulates intracellular levels of RKIP and likely controls its degradation. Hence, CEP290’s involvement in intracellular signaling and in protein degradation pathways may be linked to cilia formation or function. However, further investigations are necessary to establish such links and to further delineate the roles of TZ proteins in regulating protein trafficking and photoreceptor OS development and function.
Acknowledgement
This work is supported by grants from the National Institutes of Health, Foundation Fighting Blindness, and Worcester foundation (to HK).
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