Molecular and Cellular Mechanisms of Vertebrate Retinal Development and Retinal Disease
Vertebrate photoreceptors are specialized light sensing neurons that have a morphology and die in retinal degeneration diseases, including macular degeneration, retinitis pigmentosa and many other inherited retinal degenerations. The photoreceptor outer segment is a highly modified cilium where photons of light are captured and transduced into changes in membrane potential that alter synaptic neurotransmitter release. The rod outer segment (ROS) has the typical ciliary axoneme but, in addition, alongside the axoneme, are hundreds of densely packed, stacked, intramembranous discs (1300-1500 discs in a human ROS). Although the ROS is a (modified) nonmotile cilium, the volume of a human ROS is approximately 250-300 times larger than a typical mammalian primary nonmotile cilium and the amount of membrane in the ROS is nearly 1000 times more than in a typical cilium. While there are certainly common mechanisms that contribute to the formation and maintenance of primary cilia and photoreceptor outer segments, it is likely that the formation of photoreceptor outer segments requires additional mechanisms considering the significant added structural components (e.g. the discs) and its large volume compared to the primary cilium. The molecular mechanisms that contribute to vertebrate photoreceptor outer segment morphogenesis and disc formation are poorly understood. In many mouse models of human retinal degeneration diseases, ROSs progressively shorten before photoreceptors die. This observation suggests that there might be a causal link between outer segment size and photoreceptor viability. In this case, it might possible to prolong photoreceptor function and survival if shortening of outer segments could be inhibited.
Another major difference between photoreceptor outer segments and primary cilia is that the outer segment is continuously regenerated or renewed throughout the life of the animal through the combined processes of proximal outer segment growth and distal outer segment shedding (Young, 1967; Young and Droz, 1968; Young and Bok, 1969; Young, 1971). Photoreceptors renew their outer segments probably because there is no mechanism to retrieve and replace worn disc membrane and its resident proteins through the narrow connecting cilium. Although the length of the primary cilium can change, this appears to be through the addition or removal of tubulin dimers at the axonemal tip of the cilium and not through a process of tip-shedding (see reviews, Miyoshi et al., 2011; Ishikawa and Marshall, 2011). Although the fascinating and important process of ROS renewal was described over 40 years ago, progress has been very slow in identifying the molecular mechanisms that regulate the processes of growth and shedding. We recently developed a powerful new method to rapidly measure ROS renewal in rod photoreceptors (Willoughby and Jensen, 2012) and this uniquely positions us to begin identifying important mechanisms of ROS renewal and, importantly, will allow us to test whether it is possible to prolong vision by maintaining outer segment length in retinal degeneration diseases by stimulating growth or suppressing shedding.
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