Aipl1 is required for cone photoreceptor function and survival through the stability of Pde6c and Gc3 in zebrafish

Iribarne, María; Nishiwaki, Yuko; Nakamura, Shohei; Araragi, Masato; Oguri, Eri; Masai, Ichiro

doi:10.1038/srep45962

Cited by 17 publications

(24 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…6C), a prominent feature of activated microglia (30,34,61). Interestingly, low levels of multiple cone-specific genes, such as Aipl1, Chrnb4, and Gnb3, were observed in microglia from AAV8-GFP-treated retinas (62)(63)(64), potentially due to phagocytosis of dying cones or cone fragments. Fewer of these transcripts were detected in microglia from AAV8-sCX3CL1-treated retinas, hinting that sCX3CL1 might affect the digestion of phagocytosed materials.…”

Section: Microglia Reside In the Photoreceptor Layer Throughout Conementioning

confidence: 99%

Soluble CX3CL1 gene therapy improves cone survival and function in mouse models of retinitis pigmentosa

Wang

Xue

Rana

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Retinitis pigmentosa (RP) is a disease that initially presents as night blindness due to genetic deficits in the rod photoreceptors of the retina. Rods then die, causing dysfunction and death of cone photoreceptors, the cell type that mediates high acuity and color vision, ultimately leading to blindness. We investigated immune responses in mouse models of RP and found evidence of microglia activation throughout the period of cone degeneration. Using adeno-associated vectors (AAVs), delivery of genes encoding microglial regulatory signals led to the identification of AAV serotype 8 (AAV8) soluble CX3CL1 (sCX3CL1) as a promising therapy for degenerating cones. Subretinal injection of AAV8-sCX3CL1 significantly prolonged cone survival in three strains of RP mice. Rescue of cones was accompanied by improvements in visual function. AAV8-sCX3CL1 did not affect rod survival, microglia localization, or inflammatory cytokine levels in the retina. Furthermore, although RNA sequencing of microglia demonstrated marked transcriptional changes with AAV8-sCX3CL1, pharmacological depletion of up to ∼99% of microglia failed to abrogate the effect of AAV8-sCX3CL1 on cone survival. These findings indicate that AAV8-sCX3CL1 can rescue cones in multiple mouse models of RP via a pathway that does not require normal numbers of microglia. Gene therapy with sCX3CL1 is a promising mutation-independent approach to preserve vision in RP and potentially other forms of retinal degeneration. retinitis pigmentosa | cone degeneration | gene therapy | CX3CL1 | microglia

show abstract

Section: Microglia Reside In the Photoreceptor Layer Throughout Conementioning

confidence: 99%

Soluble CX3CL1 gene therapy improves cone survival and function in mouse models of retinitis pigmentosa

Wang

Xue

Rana

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Acute damage leads to rapid loss of retinal cells that resemble traumatic injury in human patients. On the other hand, retinal regeneration studies using chronic damage models in the zebrafish retinas are limited (Iribarne, Hyde, & Masai, 2019;Iribarne et al, 2017;Morris, Scholz, Brockerhoff, & Fadool, 2008;Nishiwaki et al, 2008;Sherpa, Hunter, Frey, Robison, & Stenkamp, 2011;Turkalj et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Inflammation modulates regeneration in the acute or chronically damaged zebrafish retina

Iribarne

Hyde

2021

Preprint

Self Cite

View full text Add to dashboard Cite

Unlike mammals, zebrafish regenerate in response to retinal damage. Because microglia are activated by retinal damage, we investigated their role during regeneration following acute or chronic damage. At three weeks-post-fertilization (wpf), fish exhibiting NMDA-induced acute damage or cone photoreceptor-specific chronic degeneration, the gold rush (gosh) mutant, displayed reactive microglia and Müller glia proliferation. Retinas treated to inhibit the immune response lacked reactive microglia and possessed fewer PCNA-positive cells, while LPS treatment increased microglia and PCNA-labeled cells. NMDA-injured retinas upregulated the expression of il-1β and tnf-α pro-inflammatory cytokine genes, followed by increased expression of il-10 and arg1 anti-inflammatory/remodeling cytokine genes. An early and transiently TNF-α pro-inflammatory microglia population was identified in the NMDA-damaged retina. In contrast, gosh mutant retinas exhibited a mild increase of pro-inflammatory cytokine gene expression concurrently with a greater increased in anti-inflammatory/remodeling cytokine gene expression. Few TNF-α pro-inflammatory microglia were observed in the gosh retina. How inflammation regulates regeneration in zebrafish would provide important clues towards improving the therapeutic strategies for repairing injured mammalian tissues.

show abstract

“…The PDE6C protein is chaperoned to the cone outer segment by AIPL1 and Pγ where it ultimately joins the other subunits of the enzyme on outer segment disks, which are infoldings of the cone outer segment membrane (20, 35, 36). Mutations in this gene are associated with achromatopsia in several human pedigrees, accounting for about 1% of clinical cases (17).…”

Section: Discussionmentioning

confidence: 99%

A nonhuman primate model of inherited retinal disease

Moshiri

Chen

Kim

et al. 2019

Journal of Clinical Investigation

View full text Add to dashboard Cite

Inherited retinal degenerations are a common cause of untreatable blindness worldwide, with retinitis pigmentosa and cone dystrophy affecting approximately 1 in 3500 and 1 in 10,000 individuals, respectively. A major limitation to the development of effective therapies is the lack of availability of animal models that fully replicate the human condition. Particularly for cone disorders, rodent, canine, and feline models with no true macula have substantive limitations. By contrast, the cone-rich macula of a nonhuman primate (NHP) closely mirrors that of the human retina. Consequently, well-defined NHP models of heritable retinal diseases, particularly cone disorders that are predictive of human conditions, are necessary to more efficiently advance new therapies for patients. We have identified 4 related NHPs at the California National Primate Research Center with visual impairment and findings from clinical ophthalmic examination, advanced retinal imaging, and electrophysiology consistent with achromatopsia. Genetic sequencing confirmed a homozygous R565Q missense mutation in the catalytic domain of PDE6C, a cone-specific phototransduction enzyme associated with achromatopsia in humans. Biochemical studies demonstrate that the mutant mRNA is translated into a stable protein that displays normal cellular localization but is unable to hydrolyze cyclic GMP (cGMP). This NHP model of a cone disorder will not only serve as a therapeutic testing ground for achromatopsia gene replacement, but also for optimization of gene editing in the macula and of cone cell replacement in general.

show abstract

Aipl1 is required for cone photoreceptor function and survival through the stability of Pde6c and Gc3 in zebrafish

Cited by 17 publications

References 40 publications

Soluble CX3CL1 gene therapy improves cone survival and function in mouse models of retinitis pigmentosa

Soluble CX3CL1 gene therapy improves cone survival and function in mouse models of retinitis pigmentosa

Inflammation modulates regeneration in the acute or chronically damaged zebrafish retina

A nonhuman primate model of inherited retinal disease

Contact Info

Product

Resources

About