Ординатура / Офтальмология / Английские материалы / Recent Advances in Retinal Degeneration_LaVail, Hollyfield, Anderson _2008

Fig. 3 Changes of ROS induced by CNTF and light exposure. CNTF induced a shortening of ROS with narrow regions along ROS length 6 days after treatment, which completely recovered 3 weeks after treatment (A). No alteration was seen in eyes treated with PBS (A). A shortening of ROS was seen after 7 days of light exposure (400 lx, 10 hr daily) (B). The ROS length recovered to normal after 7 days in cyclic 50 lx light (B). Scale bar: 10 m. Modified from Wen et al., (2006) ( c 2006 by the Society for Neuroscience)

4 CNTFand Light-induced Changes in Rod Outer Segments

Six days after CNTF treatment, the length of rod outer segments (ROS) in CNTFtreated eyes was (15.38 ± 1.39 m, mean ± SD, n = 13), shortened by about half (46% p < 0.0001, Student t test) compared to that (28.31 ± 2.72 m, mean ± SD, n = 13) in the PBS-treated eye (Fig. 3A). The shape of the ROS in CNTF-treated eye became irregular with narrow regions along the length (Fig. 3A), which was not seen in the PBS-treated eye. Changes in ROS length and shape fully recovered 21 days after treatment (Fig. 3A).

A shortening of ROS comparable to that in CNTF-treated animals was observed in retinas that had received 10 hr daily light exposure (400 lx) for 7 days (Fig. 3B). The shape of the ROS also became somewhat irregular (Fig. 3B). These changes were fully recovered after 7 days in the normal cyclic habitat illuminance of 50 lx (Fig. 3B).

5 Discussion

We have demonstrated that CNTF treatment induces a series of biochemical and morphological changes in rod photoreceptors, which work in concert to down regulate the phototransduction machinery, leading to a lower photoresponsiveness. As a result, the amplitudes of the ERG a- and b-waves are lower in CNTF-treated retinas at a given intensity of stimulus. These biochemical and morphological changes in photoreceptors as well as changes in the ERG waves are fully reversible.

Photoreceptors are not directly responsive to CNTF. The effects of CTNF must be mediated through cells that are directly responsive to CNTF. In the retina, Müller cells directly respond to CNTF (Wen et al., 2006; Peterson et al., 2000). It is therefore likely that they are the mediators. In this scenario, CNTF activates Müller cells, which in turn send signals to rods (Fig. 4). The nature of the signals from Müller

RPE cells (Young and Bok, 1969). Penn and Williams (Penn and Williams, 1986) offered the photostasis hypothesis to explain the light-induced adjustment in photoreceptors and the role ROS renewal plays. They proposed that the continual renewal of ROS allows rods to adjust the ROS length and rhodopsin content to a new light environment by regulating the rates of disk addition and removal. They further hypothesized that the adjustment is to allow the retina to catch a constant number of photons per day regardless of the light conditions the animal is chronically exposed to. In other words, there is a “set point” toward which rods adjust their photoncatching apparatus in changing light conditions. In albino rats, the daily quota of photons for a retina is about 1016 (Penn and Williams, 1986). Although numerous studies have provided evidence supporting this hypothesis, some fundamental questions remain. It is not clear how the number of photons captured by the entire retina is counted; where the photon counting mechanism is located; and how the information is fed back to individual photoreceptors so they can adjust their phototransduction machinery accordingly. Since intravitreal administration of CNTF regulates the phototransduction machinery, the regulatory mechanism should be inside the retina and input from outside the retina is not required. If the mechanism mediating the effects of CNTF is the same that mediates light-induced photoplasticity, then the mechanism of photostasis must be located inside the retina. We therefore hypothesize that Müller cells are the photon counters. They may integrate information from photoreceptors and circadian information from photosensitive ganglion cells (Berson et al., 2002), then signal rods to regulate their phototransduction machinery.

In summary, we have demonstrated that CNTF negatively regulates rod phototransduction machinery, resulting in lower amplitude ERG waves. The similarity between CNTF treatment and light exposure strongly suggests that regulation of the phototransduction machinery by CNTF and light is through a common mechanism, the mechanism mediating photostasis in which Müller cells play a central role. Our work highlights the glia-neuron interaction to control the behavior of neurons.

Acknowledgments Supported by NIH grants EY12727, EY015289, the Foundation Fighting Blindness, and the Karl Kirchgessner Foundation.

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Galveston and was subsequently a postdoctoral fellow at Harvard Medical School. Dr. LaVail was appointed Assistant Professor of Neurology-Neuropathology at Harvard Medical School in 1973. In 1976, he moved to UCSF, where he was appointed Associate Professor of Anatomy. He was appointed to his current position in 1982, and in 1988, he also became director of the Retinitis Pigmentosa Research Center at UCSF, later named the Kearn Family Center for the Study of Retinal Degeneration. Dr. LaVail has published extensively in the research areas of photoreceptor-retinal pigment epithelial cell interactions, retinal development, circadian events in the retina, genetics of pigmentation and ocular abnormalities, inherited retinal degenerations, light-induced retinal degeneration, and pharmaceutical and gene therapy for retinal degenerative diseases. He has identified several naturally occurring murine models of human retinal degenerations and has developed transgenic mouse and rat models of others. He is the author of more than 150 research publications and has edited 12 books on inherited and environmentally induced retinal degenerations. Dr. LaVail has received the Fight for Sight Citation (1976); the Sundial Award from the Retina Foundation (1976); the Friedenwald Award from the Association for Research in Vision and Ophthalmology (ARVO, 1981); two Senior Scientific Investigators Awards from Research to Prevent Blindness (1988 and 1998); a MERIT Award from the National Eye Institute (1989); an Award for Outstanding Contributions to Vision Research from the Alcon Research Institute (1990); the Award of Merit from the Retina Research Foundation (1990); the first John A. Moran Prize for Vision Research from the University of Utah (1997); the first Trustee Award from The Foundation Fighting Blindness (1998); and the Llura Liggett Gund Award from the Foundation Fighting Blindness (2007). He has served on the editorial board of Investigative Ophthalmology and Visual Science and is currently an Executive Editor of Experimental Eye Research. Dr. LaVail has been an active participant in the program committee of ARVO and has served as a Trustee (Retinal Cell Biology Section) of ARVO. He has been a member of the program committee and a Vice President of the International Society for Eye research. He has also served on the Scientific Advisory Board of the Foundation Fighting Blindness since 1973.

Joe G. Hollyfield, Ph.D., is Director of Ophthalmic Research in the Cole Eye Institute at The Cleveland Clinic Foundation, Cleveland, Ohio. He received his Ph.D. from the University of Texas at Austin and did postdoctoral work at the Hubrecht Laboratory in Utrecht, The Netherlands. He has held faculty positions at Columbia University College of Physicians and Surgeons in New York City and at Baylor College of Medicine in Houston, TX. He was Director of the Retinitis Pigmentosa Research Center in The Cullen Eye Institute at Baylor from 1978 until his move to The Cleveland Clinic Foundation in 1995. He is currently Director of the Foundation Fighting Blindness Research Center at The Cleveland Clinic Foundation. Dr. Hollyfield has published over 170 papers in the area of cell and developmental biology of the retina and retinal pigment epithelium in both normal and retinal degenerative tissue. He has edited 13 books, 12 on retinal degenerations and one destructor of the eye. Dr. Hollyfield has received the Marjorie W. Margolin Prize (1981, 1994), the Sam and Bertha Brochstein Award (1985) and the Award of Merit in Retina Research (1998) from the Retina Research Foundation;

the Olga Keith Wiess Distinguished Scholars’ Award (1981), two Senior Scientific Investigator Awards (1988, 1994) from Research to Prevent Blindness, Inc.; an award for Outstanding Contributions to Vision Research from the Alcon Research Institute (1987); the Distinguished Alumnus Award (1991) from Hendrix College, Conway, Arkansas; and the Endre A. Balazs Prize (1994) from the International Society for Eye Research (ISER). He is currently Editor-in-Chief of the journal, Experimental Eye Research published by Academic Press. Dr. Hollyfield has been active in the Association for Research in Vision and Ophthalmology (ARVO) serving on the Program Committee, as a Trustee and as President. He is also a past President and former Secretary of the International Society of Eye Research. He currently serves on the Scientific Advisory Boards of The Foundation Fighting Blindness, Research to Prevent Blindness, The Helen Keller Eye Research Foundation, The South Africa Retinitis Pigmentosa Foundation, and is Co-Chairman of the International Retinitis Pigmentosa Foundation Medical and Scientific Advisory Board.