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Functional and morphological analysis of the subretinal injection of retinal pigment epithelium cells
- MAREN ENGELHARDT, CHINATSU TOSHA, VANDA S. LOPES, BRYAN CHEN, LISA NGUYEN, STEVEN NUSINOWITZ, DAVID S. WILLIAMS
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- Journal:
- Visual Neuroscience / Volume 29 / Issue 2 / March 2012
- Published online by Cambridge University Press:
- 01 March 2012, pp. 83-93
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Replacement of retinal pigment epithelium (RPE) cells by transplantation is a potential treatment for some retinal degenerations. Here, we used a combination of invasive and noninvasive methods to characterize the structural and functional consequences of subretinal injection of RPE cells. Pigmented cells from primary cultures were injected into albino mice. Recovery was monitored over 8 weeks by fundus imaging, spectral domain optical coherence tomography (sdOCT), histology, and electroretinography (ERG). sdOCT showed that retinal reattachment was nearly complete by 1 week. ERG response amplitudes were reduced after injection, with cone-mediated function then recovering better than rod function. Photoreceptor cell loss was evident by sdOCT and histology, near the site of injection, and is likely to have been the main cause of incomplete recovery. With microscopy, injected cells were identified by the presence of apical melanosomes. They either established contact with Bruch’s membrane, and thus became part of the RPE monolayer, or were located on the apical surface of the host’s cells, resulting in apposition of the basal surface of the injected cell with the apical surface of the host cell and the formation of a series of desmosomal junctions. RPE cell density was not increased, indicating that the incorporation of an injected cell into the RPE monolayer was concomitant with the loss of a host cell. The transplanted and remaining host cells contained large vacuoles of ingested debris as well as lipofuscin-like granules, suggesting that they had scavenged the excess injected and host cells, and were stressed by the high digestive load. Therefore, although significant functional and structural recovery was observed, the consequences of this digestive stress may be a concern for longer-term health, especially where RPE cell transplantation is used to treat diseases that include lipofuscin accumulation as part of their pathology.
The nob2 mouse, a null mutation in Cacna1f: Anatomical and functional abnormalities in the outer retina and their consequences on ganglion cell visual responses
- BO CHANG, JOHN R. HECKENLIVELY, PHILIPPA R. BAYLEY, NICHOLAS C. BRECHA, MURIEL T. DAVISSON, NORM L. HAWES, ARLENE A. HIRANO, RONALD E. HURD, AKIHIRO IKEDA, BRITT A. JOHNSON, MAUREEN A. MCCALL, CATHERINE W. MORGANS, STEVE NUSINOWITZ, NEAL S. PEACHEY, DENNIS S. RICE, KIRSTAN A. VESSEY, RONALD G. GREGG
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- Journal:
- Visual Neuroscience / Volume 23 / Issue 1 / January 2006
- Published online by Cambridge University Press:
- 09 March 2006, pp. 11-24
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Glutamate release from photoreceptor terminals is controlled by voltage-dependent calcium channels (VDCCs). In humans, mutations in the Cacna1f gene, encoding the α1F subunit of VDCCs, underlie the incomplete form of X-linked congenital stationary night blindness (CSNB2). These mutations impair synaptic transmission from rod and cone photoreceptors to bipolar cells. Here, we report anatomical and functional characterizations of the retina in the nob2 (no b-wave 2) mouse, a naturally occurring mutant caused by a null mutation in Cacna1f. Not surprisingly, the b-waves of both the light- and dark-adapted electroretinogram are abnormal in nob2 mice. The outer plexiform layer (OPL) is disorganized, with extension of ectopic neurites through the outer nuclear layer that originate from rod bipolar and horizontal cells, but not from hyperpolarizing bipolar cells. These ectopic neurites continue to express mGluR6, which is frequently associated with profiles that label with the presynaptic marker Ribeye, indicating potential points of ectopic synapse formation. However, the morphology of the presynaptic Ribeye-positive profiles is abnormal. While cone pedicles are present their morphology also appears compromised. Characterizations of visual responses in retinal ganglion cells in vivo, under photopic conditions, demonstrate that ON-center cells have a reduced dynamic range, although their basic center-surround organization is retained; no alteration in the responses of OFF-center cells was evident. These results indicate that nob2 mice are a valuable model in which to explore the pathophysiological mechanisms associated with Cacna1f mutations causing CSNB2, and the subsequent effects on visual information processing. Further, the nob2 mouse represents a model system in which to define the signals that guide synapse formation and/or maintenance in the OPL.
Mouse models of ocular diseases
- B. CHANG, N.L. HAWES, R.E. HURD, J. WANG, D. HOWELL, M.T. DAVISSON, T.H. RODERICK, S. NUSINOWITZ, J.R. HECKENLIVELY
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- Journal:
- Visual Neuroscience / Volume 22 / Issue 5 / September 2005
- Published online by Cambridge University Press:
- 06 December 2005, pp. 587-593
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The Jackson Laboratory, having the world's largest collection of mouse mutant stocks and genetically diverse inbred strains, is an ideal place to discover genetically determined eye variations and disorders. In this paper, we list and describe mouse models for ocular research available from Mouse Eye Mutant Resource at The Jackson Laboratory. While screening mouse strains and stocks at The Jackson Laboratory (TJL) for genetic mouse models of human ocular disorders, we have identified numerous spontaneous or naturally occurring mutants. We characterized these mutants using serial indirect ophthalmoscopy, fundus photography, electroretinography (ERG) and histology, and performed genetic analysis including linkage studies and gene identification. Utilizing ophthalmoscopy, electroretinography, and histology, to date we have discovered 109 new disorders affecting all aspects of the eye including the lid, cornea, iris, lens, and retina, resulting in corneal disorders, glaucoma, cataracts, and retinal degenerations. The number of known serious or disabling eye diseases in humans is large and affects millions of people each year. Yet research on these diseases frequently is limited by the obvious restrictions on studying pathophysiologic processes in the human eye. Likewise, many human ocular diseases are genetic in origin, but appropriate families often are not readily available for genetic studies. Mouse models of inherited ocular disease provide powerful tools for rapid genetic analysis, characterization, and gene identification. Because of the great similarity among mammalian genomes, these findings in mice have direct relevance to the homologous human conditions.