Rod vs. Cone Regeneration in the Teleost Retina

By Ingrid Tower

It’s 4am and you’ve gotta pee. You sit up on your bed and and search for the outlet to insert your lamp plug, because you still haven’t fixed the on/off switch. Can’t find it. Great. You must now fumble through the dark to find your way to your oh-so-far-off door.  Relax. Take it easy. Remember: you’ve got your friends, rod and cone photoreceptors in your retina, to help you out.

Rods and cones are the classic types of photosensitive cells, photoreceptors, in the retina of the vertebrate eye. Rods and cones are located in the outermost part of the retina (farthest away from the lens) and share similar methods for interpreting light signals. Light hits the photoreceptors, causes a conformational change in a photosensitive pigment, and converts the light signal into a neural signal that can travel up the optic nerve into the brain for processing. However, rods and cones are sensitive to different characteristics of light. This difference is what allows us to adjust our eyes to the room’s darkness AND see what color the bathroom rug is. How are they different exactly? Rods are most sensitive to light and dark changes, shape and movement, and contain only one type of photosensitive pigment, called rhodopsin. Rod’s high sensitivity and their uniform presence throughout the retina makes them the most responsible for vision at low light levels, also known as scotopic vision). In fact, they are believed to be one-thousand times more sensitive to photons than cones (Normann & Werblin, 1974)! Even though rods can tell us a lot about what shapes makeup our room, they’re not so great at telling us what colors those shapes are. That’s where cones come in. The photosensitive pigments in individual cones respond to one of three wavelength ranges, longer wavelengths, sometimes referred to as red, middle wavelengths (green), and shorter wavelengths (blue) (Allen et al., 2011). That’s right, we only need three cones to have such impressive vision! Cones photosensitive pigments, however, can only be activated with bright light, answering the eternal mystery of colorless nights that’s always plagued you.

In addition to the light-sensitive rod and cone photoreceptors, the retina contains four basic classes of neurons- horizontal, bipolar, amacrine, and ganglion cells- and another specialized cell called a Müller glial cell. To fit all these cells and to ensure communication between them, the retina must be efficiently organized. Evolution has created the solution: stratified layers. These neurons are arranged into three cellular (nuclear) layers that are separated by their interacting synapses (plexiform layers) (Dowling et al., 1966). The photoreceptors lie within the light-detecting outer-most layer, the outer nuclear layer (ONL).  In between this layer and the more internally-located layer, the inner nuclear layer (INL), is the outer plexiform layer (OPL). The zebrafish retinal distribution is very similar to this human retinal organization, making zebrafish an exceptional model system for studies of retinal development and degeneration (Fadool & Dowling, 2008).

Diseases that result in the loss of cone photoreceptors, such as Leber congenital amaurosis (LCA), age-related macular degeneration, and various kinds of inherited rod and cone retinal degenerations, consequently lead to severe visual impairment or blindness (Morrow et al., 1998). Many researchers believe that the key to treating irreversible retinal degeneration is finding a proper retinal stem cell treatment that can encourage photoreceptor regeneration. Unlike the mammalian eye, the zebrafish eye is actually able to regenerate retinal cells after injury (Otteson & Hitchcock, 2003; Fadool, 2003). Zebrafish rod regeneration is mediated in part by a group of specialized cells located in the ONL called rod progenitor cells (Otteson & Hitchcock, 2003). Cells may be called rod progenitor cells if they show expression of 5-bromo-2-deoxyuridine (BrdU), a general indicator of cell growth, and are located in the ONL. Rod progenitor cells branch out from a group of supposed stem cells in the INL (Raymond & Rivlin, 1987; Julian et al., 1998; Otteson et al., 2001). It has been shown that these stem cells could result from a fascinating metamorphosis by Müller glia. Müller glia cells have been shown to undergo reversal of differentiation after acute retinal damage to mediate selective cell growth. At this stage, the Müller glia cell is less specialized and capable of dividing and differentiating into a number of retinal cell types (Bernardos et al., 2007).  In 2007, a team of researchers decided to delve deep into the zebrafish eye to uncover more retinal regeneration mechanisms that can help treat degeneration. But, in order to do this, they had to create a new breed of tools.

There has been a plethora of research dedicated to analyzing zebrafish photoreceptor regeneration after induced retinal damage. However, the majority of the methods used to acutely damage the retina have been non-specific in that they impact both rods and cones. Therefore, it is impossible to determine whether the reported increase in INL cells is a reaction to rod, cone, or other collateral damage (Morris et al., 2007). Taking a different approach, Ann Morris and  colleagues bred an army of genetically altered zebrafish, XOPS-mCFP, that displayed selective degeneration of rod photoreceptors through genetic implantation of a rod-targeted toxic protein. Their other line of designed zebrafish showed specific cone degeneration as a result of mutation in the pde6c gene, giving them a very appropriate name: pde6w59 mutants.  pde6w59 mutants showed an increase in BrdU+ cells in the INL and the base of the ONL compared to wild-type zebrafish, the proposed locations of retinal stem cells and rod progenitor cells, respectively. Interestingly, the progenitor cells in the INL had Müller glia cell characteristics, indicating that the proliferative response to selective degeneration in the INL of pde6w59 mutants involves the intriguing Müller glia cell type (Morris et al., 2007).  Even more fascinating, the rod-degenerated zebrafish line, XOPS-mCFP, also showed an increase in proliferation (increase in BrdU+ cells) compared to wild-type but this increase was not reliant on Müller glia cell activation in the INL (Morris et al., 2007). Instead, rod degeneration seemed to activate rapid growth of progenitor populations in the ONL. This growing ONL cell population expressed the transcription factor Nr2e3, an indicator of rod determination, showing that they were infact rod progenitors. In addition, both mutant lines still showed significant proliferative responses as early as 7 days post fertilization (dpf). These results show that response to photoreceptor degradation is specific to the photoreceptor type being affected. Morris and coworkers hypothesized that these differing proliferative reactions could be a result of Müller glia cells introducing two different stem cell lines, one producing a rod-lineage and the other cones and inner retinal neurons They also suggest the possibility of a single population of INL stem cells generating progenitor cells, a subset of which quickly expresses rod-determination, as indicated by their Nr2e3-expression findings (Morris et al., 2007). All in all, these researchers present interesting insight into a photoreceptor cell-specific treatment following retinal damage in humans. If one day you stumble into the bathroom to find the color of the bathroom rug duller or the toilet a bit misshapen, fear not, a cure is coming.

All the primary research papers cited in the article are listed below. You can copy and paste them into PubMed to read the entire article, if you’re so inclined.

Allen A., Brown T., Lucas R. (2011) A Distinct Contribution of Short-Wavelength-Sensitive Cones to Light-Evoked Activity in the Mouse Pretectal Olivary Nucleus (2011) The Journal of Neuroscience: 31(46):16833–16843.

Bernardos RL, Barthel LK, Meyers JR, Raymond PA. (2007) Late-stage neuronal progenitors in the retina are radial Müller glia that function as retinal stem cells. J Neurosci.:27(26):7028-40.

Dowling J.E., Boycott B.B., (1966) Organization of the Primate Retina: Electron Microscopy. Proceedings of the Royal Society of London. Series B, Biological Sciences , Vol. 166, No. 1002 (Nov. 15, 1966), pp. 80-111.

Fadool JM. 2003b. Rod genesis in the teleost retina as a model of neural stem cells. Exp Neurol 184:14–19.

Fadool JM, Dowling JE. (2008) Zebrafish: a model system for the study of eye genetics. Prog Retin Eye Res.: 27(1):89-110

Hitchcock P, Kakuk-Atkins L. 2004. The basic helix-loop- helix transcription factor neuroD is expressed in the rod lineage of the teleost retina. J Comp Neurol 477:108– 117.

Julian D, Ennis K, Korenbrot JI. (1998) Birth and fate of proliferative cells in the inner nuclear layer of the mature fish retina. J Comp Neurol 394:271–282.

Morris AC, Scholz TL, Brockerhoff SE, Fadool JM (2007) Genetic dissection reveals two separate pathways for rod and cone regeneration in the teleost retina. Dev Neurobiol 68: 605–619.

Morrow E.M., Furukawa T., Cepko C.L (1998) Vertebrate photoreceptor cell development and disease. Trends Cell Biol. :353-358. doi:10.1016/S0962-8924(98)01341-5.

Normann R., Werblin F. (1974) Control of Retinal Sensitivity: Light and Dark Adaption of Vertebrate Rods and Cones. J Gen Physiol 1974 63:37-61.

Otteson DC, Hitchcock PF. (2003) Stem cells in the teleost retina: Persistent neurogenesis and injury-induced regen- eration. Vision Res 43:927–936.

Otteson DC, D’Costa AR, Hitchcock PF. (2001) Putative stem cells and the lineage of rod photoreceptors in the mature retina of the goldfish. Dev Biol 232:62–76.

Raymond PA, Rivlin PK. (1987) Germinal cells in the gold- fish retina that produce rod photoreceptors. Dev Biol 122:120–138.

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One comment

  1. Interesting!

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