Disc shedding

Disc shedding is the process by which photoreceptors in the eye are renewed. The retina contains two types of photoreceptor – rod cells and cone cells. There are about 6-7 million cones that provide color vision to the eye, and they are very concentrated in a central spot in the retina, called the macula. However, the rods are much more numerous – about 120 million – and are also more sensitive than the cones. These rods are responsible for scotopic (night) vision, our most sensitive motion detection, and our peripheral vision.

Vertebrate photoreceptors are composed of a photosensitive outer segment, an inner segment that contains the cell's metabolic machinery (endoplasmic reticulum, Golgi complex, ribosomes, mitochondria), and a synaptic terminal at which contacts with second-order neurons of the retina are made. The photosensitive outer segment is connected to the inner segment by a modified, nonmotile cilium, and consists of a series of discrete membranous discs that are apparently derived from the plasma membrane in the region of the connecting cilium.[1]

Formation and shedding

While in the rod, these discs lack any direct connection to the surface membrane (with the exception of a few recently formed basal discs that remain in continuity with the surface), the cone's photosensitive membrane is continuous with the surface membrane. The outer segment (OS) discs are densely packed with rhodopsin for high-sensitivity light detection.[2] These discs are completely replaced once every ten days and this continuous renewal continues throughout the lifetime of the sighted animal.

Opsin is synthesized on the rough endoplasmic reticulum and is an integral membrane protein. Its signal peptide is at the N-terminus but is not cleaved off. The protein is co-translationally glycosylated and the protein's carbohydrates are modified in the Golgi, before transfer to the plasma membrane. The membrane invaginates and disks bud off internally, forming the tightly packed stacks of outer segment disks. From translation of opsin to formation of the disks takes just a couple of hours.

In a famous 1967 paper – The Renewal of Photoreceptor Cell Outer Segments[3] – Professor Richard Young described his observations that new discs are assembled at the base of the outer segment – the ciliary plasmalemma – by incorporating proteins and lipids that are synthesized and transported from the inner segment. Discs mature along with their distal migration; aged discs shed at the distal tip and are engulfed by the neighboring retinal pigment epithelial cells for degradation.[2]

While many other enzymes and metabolically active proteins do turn over eventually, the photoreceptors shed the ends of their outer segments daily. Each day about one tenth of the length of the outer segment is lost, so that after ten days the entire outer segment has been replaced. In a pulse-chase experiment, Young and his co-workers showed the migration of newly synthesized opsin from the ciliary stalk to the end of the outer segment, which is ultimately phagocytosed by the RPE cell. Regulating factors are involved at each step. While disc assembly is mostly genetically controlled, disc shedding and the subsequent RPE phagocytosis appear to be regulated by environmental factors like light and temperature.[4]

Circadian rhythms that use neuromodulators such as adenosine, dopamine, glutamate, serotonin, and melatonin, rhythmically control disc shedding. Endogenous dopamine and melatonin seem to be the light and dark signal, in particular. Their method of action is simply as follows: melatonin activates rod photoreceptor disc shedding. It is synthesized by the photoreceptors at night, and is inhibited by light and dopamine. Acting in an opposite manner, dopamine, which is synthesized by amacrine and interplexiform cells is stimulated by light and inhibited by dark and melatonin. It is important to understand that, because of these rhythms, rod outer segment discs are shed at the onset of light (in the morning) and cone outer segments are shed at the onset of darkness (at dusk), both circadian processes.[5]

Traditional theories about the mechanism of disc shedding

One grey area in the entire mechanism of outer segment disc shedding is in what exactly triggers the detachment of the discs and how they are transported out of the OS and phagocytosed by the RPE cells.

Dr. Young and his team, among others, observed the disc detachment from the rod OS and through morphological studies, suggested that disc detachment preceded engulfment [3][6] and that an active process in the rod outer segment (ROS) distal tip delineates the site of attachment.

However, in a 1986 paper, an Emory professor Dr. Besharse and his team, suggested that the distinction between the processes of disc detachment and phagocytosis was made ambiguous by the observation of pigment epithelial processes intruding into the OS during disc detachment. They documented the ultrastructural changes that occur within the photoreceptor OS and the RPE during photosensitive membrane turnover. They induced shedding in Xenopus laevis by adding the excitatory amino acid L-aspartate. They found that during L-aspartate-induced shedding, the RPE cells formed, on their apical domains, previously undescribed processes that were directly involved in disc phagocytosis. These processes were structurally similar to processes formed by macrophages during phagocytosis and were accordingly referred to as pseudopodia. While pseudopodial formation also occurred during a normal light-initiated shedding event, the low frequency of shedding, the asynchrony of individual shedding events and the transient appearance of the pseudopodia prevented a full appreciation of their role during normal disc schedding. The team stated that these pseudopodia were the organelles of phagocytosis and that they may play a role in disc detachment as well.

In addition, a photoreceptor-RPE interaction was proposed to play a role in determining the domains that would detach from the OS.

Another early theory proposed by Dr. Young was that, unlike rods, mature cones neither assemble new discs nor shed old ones, replacing instead only some of their molecular constituents. This idea arose from the observation that the band of radioactive protein that they injected in the two photoreceptor cells appeared at the base of the rods within hours but slowly diffused through throughout the OS. This theory, in turn, led to a proposed distinction between rods and cones based upon whether the outer segments were renewed by membrane replacement or by molecular replacement. It was supported by some findings that showed an absence of phagosomes within the RPE of several cone-dominant species. However, teams of researchers, including that of Dr. Steinberg, soon brought evidence to the table that at least some mammalian cones, like their rod counterparts, continue to assemble as well as shed their discs as a normal ongoing process.[6] The cone visual pigment is apparently based on an apoprotein component similar to rod opsin which turns over as part of the OS membrane system.[1]

Recent research about the mechanism of disc shedding

A 2007 paper offers a third new theory that builds on recent evidence that suggests that rhodopsin-deficient mice fail to develop OSS.[7][8] Researchers at Cornell hypothesized that rhodopsin itself has a role in OS biogenesis, in addition to its role as a phototransduction receptor.[2] While the molecular basis underlying rhodopsin's participation in OS development is unknown, emerging evidence suggests that rhodopsin's cytoplasmic C-terminal tail bears an “address signal” for its transport from its site of synthesis in the rod cell body to the OS.[9][10]

The regulation of intracellular membrane trafficking by protein-lipid interactions has been gaining growing attention. A famous example is that of the ability of EEA1 (early endosomal antigen 1) to tether vesicles and regulate assembly of the SNARE (soluble NSF attachment receptor) complex to promote endocytic membrane fusion.[11][12]

Similarly, the Weill Cornell researchers zeroed in on SARA – Smad anchor for receptor activation, which is also a FYVE domain protein located in early endosomes. They combined various approaches in mammalian photoreceptors to demonstrate that the rhodopsin C-terminal tail functionally interacts with SARA, thus regulating the targeting of these vesicles to nascent discs at the base of the OS. The incorporation of rhodopsin vesicles into discs completes the OS targeting of rhodopsin and directly participates in disc biogenesis.

Observe how the Besharse and others proposed models based on the morphological studies using rapid-freeze, deep-etch, and other techniques that suggested that tubule-vesicles are derived from the internalized distal ciliary membrane and/or the very basal OS plasma membrane.[13][14] However, the Cornell researchers suggest that some of the axonemal vesicles were directly shipped from the IS through the connecting cilium as SARA was detected in the connecting cilium and basal body, possibly serving as an adaptor protein participating in rhodopsin's translocation.

References

  1. 1 2 Besharse, J.C., & Pfenninger, K.H. (1980). "Membrane assembly in retinal photoreceptors: I. Freeze-fracture analysis of cytoplasmic vesicles in relationship to disc assembly", The Journal of Cell Biology, 87, 451-463.
  2. 1 2 3 Chuang, J., Zhao, Y., & Sung, C. (2007). "SARA-regulated vesicular targeting underlies formation of the light sensing organelle in mammalian rods", Cell, 130, 535-547.
  3. 1 2 Young, R.W. (1967). "The renewal of photoreceptor outer segments". The Journal of Cell Biology. 33 (1): 61–72. doi:10.1083/jcb.33.1.61. PMC 2107286. PMID 6033942.
  4. ↑ Nguyen-Legros, J., & Hicks, D. (2000). "Renewal of photoreceptor outer segments and their phagocytosis by the retinal pigment epithelium", International Review of Cytology, 196, 245-313.
  5. ↑ LaVail, M.M. (1980). "Circadian nature of rod outer segment disc shedding in the rat", Investigative Ophthalmology & Vision Science, 19(4), 407-411.
  6. 1 2 Anderson, D.H., Fisher, S.K., & Steinberg, R.H. (1978). "Mammalian cones: disc shedding, phagocytosis, and renewal", Investigative Ophthalmology & Visual Science, 17(2), 117-33.
  7. ↑ Humphries, M.M., Rancourt, D., Farrar, G.J., Kenna, P., Hazel, M., Bush, R.A., et al. (1997). "Retinopathy induced in mice by targeted disruption of the rhodopsin gene", Nat. Genet., 15, 216-219.
  8. ↑ Lem, J., Krasnoperova, N.V., Calvert, P.D., Kosaras, B., Cameron, D.A., Nicolo, M., et al. (1999). "Morphological, physiological, and biochemical changes in rhodopsin knockout mice", Proc. Natl. Acad. Sci. USA, 96, 736-741.
  9. ↑ Tai, A.W., Chuang, J.-Z., Bode, C., Wolfrum, U., & Sung, C.-H. (1999). "Rhodopsin’s carboxy-terminal cytoplasmic tail acts as a membrane receptor for cytoplasmic dynein by binding to the dynein light chain Tctex-1", Cell, 95, 779-791.
  10. ↑ Deretic, D., Williams, A.H., Ransom, N., Morel, V., Hargrave, P.A, & Arendt, A. (2005). "Rhodopsin C terminus, the site of mutations causing retinal disease, regulates trafficking by binding to ADP-ribosylation factor 4 (ARF4)", Proc. Natl. Acad. Sci. USA, 102, 3301-3306.
  11. ↑ Christoforidis, S., McBride, H.M., Burgoyne, R.D., & Zerial, M. (1999). "The Rab5 effector EEA1 is a core component of endosome docking", Nature, 297, 621-625.
  12. ↑ Simonsen, A., Gaullier, J.M., D’Arrigo, A., and Stenmark, H. (1999). "The Rab5 effector EEA1 interacts directly with syntaxin-6", Journal of Biological Chemistry, 274, 28857-28860.
  13. ↑ Miyaguchi, K., & Hashimoto, P.H. (1992). "Evidence for the transport of opsin in the connecting cilium and basal rod outer segment in rat retina: rapid-freeze, deep-etch and horseradish peroxidase labeling studies", Journal of Neurocytology, 21, 449-457.
  14. ↑ Obata, S., & Usukura, J. (1992). "Morphogenesis of the photoreceptor outer segment during postnatal development in the mouse (BALB/C) retina", Cell Tissue Res. 269, 39-48.
This article is issued from Offline. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.