scholarly journals A new mouse model for retinal degeneration due to Fam161a deficiency

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Avigail Beryozkin ◽  
Chen Matsevich ◽  
Alexey Obolensky ◽  
Corinne Kostic ◽  
Yvan Arsenijevic ◽  
...  
Keyword(s):  
Mouse Model ◽  
Retinal Degeneration ◽  
Outer Segment ◽  
Ganglion Cells ◽  
Photoreceptor Outer Segment ◽  
Tem Analysis ◽  
Retinal Degenerations ◽  
Progressive Degeneration ◽  
Transmission Electron ◽  
Lacz Staining

AbstractFAM161A mutations are the most common cause of inherited retinal degenerations in Israel. We generated a knockout (KO) mouse model, Fam161atm1b/tm1b, lacking the major exon #3 which was replaced by a construct that include LacZ under the expression of the Fam161a promoter. LacZ staining was evident in ganglion cells, inner and outer nuclear layers and inner and outer-segments of photoreceptors in KO mice. No immunofluorescence staining of Fam161a was evident in the KO retina. Visual acuity and electroretinographic (ERG) responses showed a gradual decrease between the ages of 1 and 8 months. Optical coherence tomography (OCT) showed thinning of the whole retina. Hypoautofluorescence and hyperautofluorescence pigments was observed in retinas of older mice. Histological analysis revealed a progressive degeneration of photoreceptors along time and high-resolution transmission electron microscopy (TEM) analysis showed that photoreceptor outer segment disks were disorganized in a perpendicular orientation and outer segment base was wider and shorter than in WT mice. Molecular degenerative markers, such as microglia and CALPAIN-2, appear already in a 1-month old KO retina. These results indicate that a homozygous Fam161a frameshift mutation affects retinal function and causes retinal degeneration. This model will be used for gene therapy treatment in the future.

PRCD is Concentrated at the Base of Photoreceptor Outer Segments and is Involved in Outer Segment Disc Formation

2019 ◽  
Author(s):  
Gilad Allon ◽  
Irit Mann ◽  
Lital Remez ◽  
Elisabeth Sehn ◽  
Leah Rizel ◽  
...  
Keyword(s):  
Retinal Degeneration ◽  
Knockout Mice ◽  
Outer Segment ◽  
Mouse Retina ◽  
Cone Photoreceptors ◽  
Photoreceptor Outer Segment ◽  
Photoreceptor Outer Segments ◽  
Outer Segments ◽  
Rod And Cone Photoreceptors ◽  
Disc Formation

Abstract Mutations of the PRCD gene are associated with rod-cone degeneration in both dogs and humans. Prcd is expressed in the mouse eye as early as embryonic day 14. In the adult mouse retina PRCD is expressed in the outer segments of both rod and cone photoreceptors. Immunoelectron microscopy revealed that PRCD is located at the outer segment rim, and that it is highly concentrated at the base of the outer segment. Prcd-knockout mice present with progressive retinal degeneration, starting at 20 weeks of age and onwards. This process is reflected by a significant and progressive reduction of both scotopic and photopic electroretinographic responses, and by thinning of the retina, and specifically of the outer nuclear layer, indicating photoreceptor loss. Electron microscopy revealed severe damage to photoreceptor outer segments, which is associated with immigration of microglia cells to the Prcd-knockout retina, and accumulation of vesicles in the inter-photoreceptor space. Phagocytosis of photoreceptor outer segment discs by the retinal pigmented epithelium is severely reduced. Our data show that Prcd-knockout mice serve as a good model for retinal degeneration caused by PRCD mutations in humans. Our findings in these mice support the involvement of PRCD in outer segment disc formation of both rod and cone photoreceptors. Furthermore, they suggest a feedback mechanism which coordinates the rate of photoreceptor outer segment disc formation, shedding and phagocytosis. This study has important implications for understanding the function of PRCD in the retina, as well as for future development of treatment modalities for PRCD-deficiency in humans.

scholarly journals Aberrant synaptic input to retinal ganglion cells varies with morphology in a mouse model of retinal degeneration

2014 ◽  
Vol 522 (18) ◽  
pp. 4085-4099 ◽  
Author(s):  
Christopher W. Yee ◽  
Abduqodir H. Toychiev ◽  
Elena Ivanova ◽  
Botir T. Sagdullaev
Keyword(s):  
Mouse Model ◽  
Retinal Degeneration ◽  
Retinal Ganglion Cells ◽  
Synaptic Input ◽  
Ganglion Cells ◽  
Retinal Ganglion

scholarly journals PRCD is essential for high-fidelity photoreceptor disc formation

2019 ◽  
Vol 116 (26) ◽  
pp. 13087-13096 ◽  
Author(s):  
William J. Spencer ◽  
Jin-Dong Ding ◽  
Tylor R. Lewis ◽  
Chen Yu ◽  
Sebastien Phan ◽  
...  
Keyword(s):  
Outer Segment ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
High Fidelity ◽  
Photoreceptor Outer Segment ◽  
Progressive Degeneration ◽  
Microglial Migration ◽  
Microglial Response ◽  
Interphotoreceptor Matrix ◽  
Disc Formation

Progressive rod-cone degeneration (PRCD) is a small protein residing in the light-sensitive disc membranes of the photoreceptor outer segment. Until now, the function of PRCD has remained enigmatic despite multiple demonstrations that its mutations cause blindness in humans and dogs. Here, we generated a PRCD knockout mouse and observed a striking defect in disc morphogenesis, whereby newly forming discs do not properly flatten. This leads to the budding of disc-derived vesicles, specifically at the site of disc morphogenesis, which accumulate in the interphotoreceptor matrix. The defect in nascent disc flattening only minimally alters the photoreceptor outer segment architecture beyond the site of new disc formation and does not affect the abundance of outer segment proteins and the photoreceptor’s ability to generate responses to light. Interestingly, the retinal pigment epithelium, responsible for normal phagocytosis of shed outer segment material, lacks the capacity to clear the disc-derived vesicles. This deficiency is partially compensated by a unique pattern of microglial migration to the site of disc formation where they actively phagocytize vesicles. However, the microglial response is insufficient to prevent vesicular accumulation and photoreceptors of PRCD knockout mice undergo slow, progressive degeneration. Taken together, these data show that the function of PRCD is to keep evaginating membranes of new discs tightly apposed to each other, which is essential for the high fidelity of photoreceptor disc morphogenesis and photoreceptor survival.

scholarly journals Rab28 is localised to photoreceptor outer segments, regulates outer segment shedding but is not linked to retinal degeneration in zebrafish

2019 ◽  
Author(s):  
Stephen P. Carter ◽  
Ailís L. Moran ◽  
David Matallanas ◽  
Gavin J. McManus ◽  
Oliver E. Blacque ◽  
...  
Keyword(s):  
Retinal Degeneration ◽  
Outer Segment ◽  
Membrane Surface ◽  
Photoreceptor Outer Segment ◽  
Membrane Surface Area ◽  
Photoreceptor Outer Segments ◽  
Outer Segments ◽  
Retinal Structure ◽  
Phototransduction Cascade ◽  
Shed Light

AbstractThe photoreceptor outer segment is the canonical example of a modified and highly specialised cilium, with an expanded membrane surface area in the form of discs or lamellae for efficient light detection. Many ciliary proteins are essential for normal photoreceptor function and cilium dysfunction often results in retinal degeneration leading to impaired vision. Herein, we investigate the function and localisation of the ciliary G-protein RAB28 in zebrafish cone photoreceptors. CRISPR-Cas9 generated rab28 mutant zebrafish display a reduction in shed outer segment material in the RPE at 1 month post fertilisation (mpf), but otherwise normal retinal structure and visual function up to 12 mpf. Cone photoreceptor-specific transgenic reporter lines show Rab28 localises almost exclusively to outer segments, independently of nucleotide binding. Co-immunoprecipitation analysis demonstrates tagged Rab28 interacts with components of the phototransduction cascade, including opsins, Phosphodiesterase 6C and Guanylate Cyclase 2D. Our data shed light on RAB28 function in cones and provide a model for RAB28-associated cone-rod dystrophy.

scholarly journals CEP290 myosin-tail homology domain is essential for protein confinement between inner and outer segments in photoreceptors

2019 ◽  
Author(s):  
Poppy Datta ◽  
Brandon Hendrickson ◽  
Sarah Brendalen ◽  
Avri Ruffcorn ◽  
Seongjin Seo
Keyword(s):  
Membrane Proteins ◽  
Retinal Degeneration ◽  
Protein Trafficking ◽  
Outer Segment ◽  
Retinal Degenerations ◽  
Outer Segments ◽  
Disease Mechanisms ◽  
Initial Stage ◽  
Conditional Mutant ◽  
Ciliary Protein

ABSTRACTMutations in CEP290 cause various ciliopathies involving retinal degeneration. CEP290 proteins localize to the ciliary transition zone and are thought to act as a gatekeeper that controls ciliary protein trafficking. However, precise roles of CEP290 in photoreceptors and pathomechanisms of retinal degeneration in CEP290-associated ciliopathies are not sufficiently understood. Using Cep290 conditional mutant mice, in which the C-terminal myosin-tail homology domain is disrupted after the connecting cilium is assembled, we show that CEP290, more specifically the myosin-tail homology domain of CEP290, is essential for protein confinement between the inner and the outer segments. Inner segment plasma membrane proteins including STX3, SNAP25, and IMPG2 rapidly accumulate in the outer segment upon disruption of the myosin-tail homology domain. In contrast, localization of endomembrane proteins is not altered. Trafficking and confinement of most outer segment-resident proteins appear to be unaffected or only minimally affected in this mouse model. One notable exception is RHO, which exhibits severe mislocalization to inner segments from the initial stage of degeneration. Similar mislocalization phenotypes were observed in rd16 mice. These results suggest that failure of protein confinement at the connecting cilium and consequent accumulation of inner segment membrane proteins in the outer segment combined with insufficient RHO delivery is part of the disease mechanisms that cause retinal degeneration in CEP290-associated ciliopathies. Our study provides insights into the pathomechanisms of retinal degenerations associated with compromised ciliary gates.

scholarly journals AHI1 is required for photoreceptor outer segment development and is a modifier for retinal degeneration in nephronophthisis

2010 ◽  
Vol 42 (2) ◽  
pp. 175-180 ◽  
Author(s):  
Carrie M Louie ◽  
Gianluca Caridi ◽  
Vanda S Lopes ◽  
Francesco Brancati ◽  
Andreas Kispert ◽  
...  
Keyword(s):  
Retinal Degeneration ◽  
Outer Segment ◽  
Photoreceptor Outer Segment

scholarly journals Reduced Disc Shedding and Phagocytosis of Photoreceptor Outer Segment Contributes to Kava Kava Extract–induced Retinal Degeneration in F344/N Rats

2018 ◽  
Vol 46 (5) ◽  
pp. 564-573 ◽  
Author(s):  
Haruhiro Yamashita ◽  
Mark J. Hoenerhoff ◽  
Keith R. Shockley ◽  
Shyamal D. Peddada ◽  
Kevin E. Gerrish ◽  
...  
Keyword(s):  
Retinal Degeneration ◽  
Outer Segment ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Morphological Alteration ◽  
Albino Rats ◽  
Photoreceptor Outer Segment ◽  
Photoreceptor Layer ◽  
Epithelial Homeostasis ◽  
Kava Kava

There was a significant increase in the incidence of retinal degeneration in F344/N rats chronically exposed to Kava kava extract (KKE) in National Toxicology Program (NTP) bioassay. A retrospective evaluation of these rat retinas indicated a similar spatial and morphological alteration as seen in light-induced retinal degeneration in albino rats. Therefore, it was hypothesized that KKE has a potential to exacerbate the light-induced retinal degeneration. To investigate the early mechanism of retinal degeneration, we conducted a 90-day F344/N rat KKE gavage study at doses of 0 and 1.0 g/kg (dose which induced retinal degeneration in the 2-year NTP rat KKE bioassay). The morphological evaluation indicated reduced number of phagosomes in the retinal pigment epithelium (RPE) of the superior retina. Transcriptomic alterations related to retinal epithelial homeostasis and melatoninergic signaling were observed in microarray analysis. Phagocytosis of photoreceptor outer segment by the underlying RPE is essential to maintain the homeostasis of the photoreceptor layer and is regulated by melatonin signaling. Therefore, reduced photoreceptor outer segment disc shedding and subsequent lower number of phagosomes in the RPE and alterations in the melatonin pathway may have contributed to the increased incidences of retinal degeneration observed in F344/N rats in the 2-year KKE bioassay.

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