scholarly journals KIT ligand protects against both light-induced and genetic photoreceptor degeneration

2019 ◽  
Author(s):  
Huirong Li ◽  
Lili Lian ◽  
Bo Liu ◽  
Yu Chen ◽  
Jinglei Yang ◽  
...  
Keyword(s):  
Photoreceptor Cell ◽  
Photoreceptor Cells ◽  
Nuclear Accumulation ◽  
Tyrosine Kinase Receptor ◽  
Light Damage ◽  
Cell Degeneration ◽  
Kit Ligand ◽  
Retinal Degenerative Diseases ◽  
Experimental Expression ◽  
Inherited Retinal Degeneration

AbstractPhotoreceptor cell degeneration is a major cause of blindness and a considerable health burden during aging but effective therapeutic or preventive strategies have not so far become commercially available. Here we show in mouse models that signaling through the tyrosine kinase receptor KIT protects photoreceptor cells against both light-induced and inherited retinal degeneration. Upon light damage, photoreceptor cells upregulate Kit ligand (KITL) and activate KIT signaling, which in turn induces nuclear accumulation of the transcription factor NRF2 and stimulates the expression of the antioxidant gene Hmox1. Conversely, a viable Kit mutation promotes light-induced photoreceptor damage, which is reversed by experimental expression of Hmox1. Furthermore, overexpression of KITL from a viral AAV8 vector prevents photoreceptor cell death and partially restores retinal function after light damage or in genetic models of human retinitis pigmentosa. Hence, application of KITL may provide a novel therapeutic avenue for prevention or treatment of retinal degenerative diseases.

scholarly journals KIT ligand protects against both light-induced and genetic photoreceptor degeneration

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Huirong Li ◽  
Lili Lian ◽  
Bo Liu ◽  
Yu Chen ◽  
Jinglei Yang ◽  
...  
Keyword(s):  
Photoreceptor Cells ◽  
Nuclear Accumulation ◽  
Tyrosine Kinase Receptor ◽  
Light Damage ◽  
Photoreceptor Degeneration ◽  
Kit Mutation ◽  
Kit Ligand ◽  
Retinal Degenerative Diseases ◽  
Experimental Expression ◽  
Inherited Retinal Degeneration

Photoreceptor degeneration is a major cause of blindness and a considerable health burden during aging but effective therapeutic or preventive strategies have not so far become readily available. Here, we show in mouse models that signaling through the tyrosine kinase receptor KIT protects photoreceptor cells against both light-induced and inherited retinal degeneration. Upon light damage, photoreceptor cells upregulate Kit ligand (KITL) and activate KIT signaling, which in turn induces nuclear accumulation of the transcription factor NRF2 and stimulates the expression of the antioxidant gene Hmox1. Conversely, a viable Kit mutation promotes light-induced photoreceptor damage, which is reversed by experimental expression of Hmox1. Furthermore, overexpression of KITL from a viral AAV8 vector prevents photoreceptor cell death and partially restores retinal function after light damage or in genetic models of human retinitis pigmentosa. Hence, application of KITL may provide a novel therapeutic avenue for prevention or treatment of retinal degenerative diseases.

scholarly journals SARM1 deficiency promotes rod and cone photoreceptor cell survival in a model of retinal degeneration

2020 ◽  
Vol 3 (5) ◽  
pp. e201900618 ◽  
Author(s):  
Ema Ozaki ◽  
Luke Gibbons ◽  
Nuno GB Neto ◽  
Paul Kenna ◽  
Michael Carty ◽  
...  
Keyword(s):  
Cell Survival ◽  
Retinal Degeneration ◽  
Photoreceptor Cell ◽  
Neuronal Cell ◽  
Photoreceptor Cells ◽  
Cone Photoreceptor ◽  
Double Knockout ◽  
Cell Degeneration ◽  
Photoreceptor Layer ◽  
Dependent Cell

Retinal degeneration is the leading cause of incurable blindness worldwide and is characterised by progressive loss of light-sensing photoreceptors in the neural retina. SARM1 is known for its role in axonal degeneration, but a role for SARM1 in photoreceptor cell degeneration has not been reported. SARM1 is known to mediate neuronal cell degeneration through depletion of essential metabolite NAD and induction of energy crisis. Here, we demonstrate that SARM1 is expressed in photoreceptors, and using retinal tissue explant, we confirm that activation of SARM1 causes destruction of NAD pools in the photoreceptor layer. Through generation of rho−/−sarm1−/− double knockout mice, we demonstrate that genetic deletion of SARM1 promotes both rod and cone photoreceptor cell survival in the rhodopsin knockout (rho−/−) mouse model of photoreceptor degeneration. Finally, we demonstrate that SARM1 deficiency preserves cone visual function in the surviving photoreceptors when assayed by electroretinography. Overall, our data indicate that endogenous SARM1 has the capacity to consume NAD in photoreceptor cells and identifies a previously unappreciated role for SARM1-dependent cell death in photoreceptor cell degeneration.

scholarly journals Activation of the molecular chaperone, sigma 1 receptor, preserves cone function in a murine model of inherited retinal degeneration

2016 ◽  
Vol 113 (26) ◽  
pp. E3764-E3772 ◽  
Author(s):  
Jing Wang ◽  
Alan Saul ◽  
Penny Roon ◽  
Sylvia B. Smith
Keyword(s):  
Retinal Degeneration ◽  
Photoreceptor Cells ◽  
Sigma 1 Receptor ◽  
Therapeutic Implications ◽  
Cellular Survival ◽  
Cone Cells ◽  
Cone Function ◽  
Sigma 1 ◽  
Retinal Degenerative Diseases ◽  
Inherited Retinal Degeneration

Retinal degenerative diseases are major causes of untreatable blindness, and novel approaches to treatment are being sought actively. Here we explored the activation of a unique protein, sigma 1 receptor (Sig1R), in the treatment of PRC loss because of its multifaceted role in cellular survival. We used Pde6βrd10 (rd10) mice, which harbor a mutation in the rod-specific phosphodiesterase gene Pde6β and lose rod and cone photoreceptor cells (PRC) within the first 6 wk of life, as a model for severe retinal degeneration. Systemic administration of the high-affinity Sig1R ligand (+)-pentazocine [(+)-PTZ] to rd10 mice over several weeks led to the rescue of cone function as indicated by electroretinographic recordings using natural noise stimuli and preservation of cone cells upon spectral domain optical coherence tomography and retinal histological examination. The protective effect appears to result from the activation of Sig1R, because rd10/Sig1R−/− mice administered (+)-PTZ exhibited no cone preservation. (+)-PTZ treatment was associated with several beneficial cellular phenomena including attenuated reactive gliosis, reduced microglial activation, and decreased oxidative stress in mutant retinas. To our knowledge, this is the first report that activation of Sig1R attenuates inherited PRC loss. The findings may have far-reaching therapeutic implications for retinal neurodegenerative diseases.

scholarly journals A rat model for retinitis pigmentosa with rapid retinal degeneration enables drug evaluation in vivo

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Chisato Inoue ◽  
Tamaki Takeuchi ◽  
Akira Shiota ◽  
Mineo Kondo ◽  
Yuji Nshizawa
Keyword(s):  
Retinitis Pigmentosa ◽  
Retinal Degeneration ◽  
Rat Model ◽  
Photoreceptor Cell ◽  
Photoreceptor Cells ◽  
Therapeutic Agents ◽  
Transgenic Rat ◽  
Cell Degeneration ◽  
Rat Strain

Abstract Background Although retinitis pigmentosa (RP) is most frequently studied in mouse models, rats, rabbits, and pigs are also used as animal models of RP. However, no studies have reported postnatal photoreceptor cell loss before complete development in these models. Here, we generated a transgenic rat strain, named the P347L rat, in which proline at position 347 in the rhodopsin protein was replaced with leucine. Results A pathological analysis of photoreceptor cells in the P347L rat model was performed, and drugs with potential use as therapeutic agents against RP were investigated. The data clearly showed rapid degeneration and elimination of the outer nuclear layer even before the photoreceptor cells were fully established in P347L rats. To test the usefulness of the P347L rat in the search for new therapeutic agents against RP, the effects of rapamycin on RP were investigated in this rat strain. The findings suggest that rapamycin promotes autophagy and autophagosomal uptake of the rhodopsin that has accumulated abnormally in the cytoplasm, thereby alleviating stress and delaying photoreceptor cell death. Conclusions In this RP model, the time to onset of retinal degeneration was less than that of previously reported RP models with other rhodopsin mutations, enabling quicker in vivo evaluation of drug efficacy. Administration of rapamycin delayed the photoreceptor cell degeneration by approximately 1 day.

scholarly journals Virus-Mediated Transduction of Murine Retina with Adeno-Associated Virus: Effects of Viral Capsid and Genome Size

2002 ◽  
Vol 76 (15) ◽  
pp. 7651-7660 ◽  
Author(s):  
Grace S. Yang ◽  
Michael Schmidt ◽  
Ziying Yan ◽  
Jonathan D. Lindbloom ◽  
Thomas C. Harding ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Photoreceptor Cells ◽  
Cell Types ◽  
Full Length ◽  
Specific Cell ◽  
Adeno Associated Virus ◽  
Gene Therapy Vectors ◽  
Retinal Degenerative Diseases ◽  
Or Gene ◽  
Half Length

ABSTRACT Gene therapy vectors based on adeno-associated viruses (AAVs) show promise for the treatment of retinal degenerative diseases. In prior work, subretinal injections of AAV2, AAV5, and AAV2 pseudotyped with AAV5 capsids (AAV2/5) showed variable retinal pigmented epithelium (RPE) and photoreceptor cell transduction, while AAV2/1 predominantly transduced the RPE. To more thoroughly compare the efficiencies of gene transfer of AAV2, AAV3, AAV5, and AAV6, we quantified, using stereological methods, the kinetics and efficiency of AAV transduction to mouse photoreceptor cells. We observed persistent photoreceptor and RPE transduction by AAV5 and AAV2 up to 31 weeks and found that AAV5 transduced a greater volume than AAV2. AAV5 containing full-length or half-length genomes and AAV2/5 transduced comparable numbers of photoreceptor cells with similar rates of onset of expression. Compared to AAV2, AAV5 transduced significantly greater numbers of photoreceptor cells at 5 and 15 weeks after surgery (greater than 1,000 times and up to 400 times more, respectively). Also, there were 30 times more genome copies in eyes injected with AAV2/5 than in eyes injected with AAV2. Comparing AAVs with half-length genomes, AAV5 transduced only four times more photoreceptor cells than AAV2 at 5 weeks and nearly equivalent numbers at 15 weeks. The enhancement of transduction was seen at the DNA level, with 50 times more viral genome copies in retinas injected with AAV having short genomes than in retinas injected with AAV containing full-length ones. Subretinal injection of AAV2/6 showed only RPE transduction at 5 and 15 weeks, while AAV2/3 did not transduce retinal cells. We conclude that varying genome length and AAV capsids may allow for improved expression and/or gene transfer to specific cell types in the retina.

scholarly journals The rat c-kit ligand, stem cell factor, induces c-kit receptor-dependent mouse mast cell activation in vivo. Evidence that signaling through the c-kit receptor can induce expression of cellular function.

1992 ◽  
Vol 175 (1) ◽  
pp. 245-255 ◽  
Author(s):  
B K Wershil ◽  
M Tsai ◽  
E N Geissler ◽  
K M Zsebo ◽  
S J Galli
Keyword(s):  
Mast Cell ◽  
Stem Cell ◽  
Mast Cells ◽  
Stem Cell Factor ◽  
Cell Activation ◽  
Mast Cell Activation ◽  
Tyrosine Kinase Receptor ◽  
Kit Ligand ◽  
Kit Receptor

Interactions between products of the mouse W locus, which encodes the c-kit tyrosine kinase receptor, and the Sl locus, which encodes a ligand for c-kit receptor, which we have designated stem cell factor (SCF), have a critical role in the development of mast cells. Mice homozygous for mutations at either locus exhibit several phenotypic abnormalities including a virtual absence of mast cells. Moreover, the c-kit ligand SCF can induce the proliferation and maturation of normal mast cells in vitro or in vivo, and also can result in repair of the mast cell deficiency of Sl/Sld mice in vivo. We now report that administration of SCF intradermally in vivo results in dermal mast cell activation and a mast cell-dependent acute inflammatory response. This effect is c-kit receptor dependent, in that it is not observed when SCF is administered to mice containing dermal mast cells expressing functionally inactive c-kit receptors, is observed with both glycosylated and nonglycosylated forms of SCF, and occurs at doses of SCF at least 10-fold lower on a molar basis than the minimally effective dose of the classical dermal mast cell-activating agent substance P. These findings represent the first demonstration in vivo that a c-kit ligand can result in the functional activation of any cellular lineage expressing the c-kit receptor, and suggest that interactions between the c-kit receptor and its ligand may influence mast cell biology through complex effects on proliferation, maturation, and function.

Control of photoreceptor cell morphology, planar polarity and epithelial integrity during Drosophila eye development

Development ◽  
2002 ◽  
Vol 129 (9) ◽  
pp. 2247-2258 ◽  
Author(s):  
Amanda T. Pickup ◽  
Michele L. Lamka ◽  
Qi Sun ◽  
Man Lun R. Yip ◽  
Howard D. Lipshitz
Keyword(s):  
Cell Fate ◽  
Cell Morphology ◽  
Photoreceptor Cell ◽  
Zinc Finger Protein ◽  
Photoreceptor Cells ◽  
Planar Polarity ◽  
Tracheal System ◽  
General Role ◽  
Epithelial Integrity ◽  
Jnk Signaling

We report that the hindsight (hnt) gene, which encodes a nuclear zinc-finger protein, regulates cell morphology, cell fate specification, planar cell polarity and epithelial integrity during Drosophila retinal development. In the third instar larval eye imaginal disc, HNT protein expression begins in the morphogenetic furrow and is refined to cells in the developing photoreceptor cell clusters just before their determination as neurons. In hnt mutant larval eye tissue, furrow markers persist abnormally posterior to the furrow, there is a delay in specification of preclusters as cells exit the furrow, there are morphological defects in the preclusters and recruitment of cells into specific R cell fates often does not occur. Additionally, genetically mosaic ommatidia with one or more hnt mutant outer photoreceptor cells, have planar polarity defects that include achirality, reversed chirality and misrotation. Mutants in the JNK pathway act as dominant suppressors of the hnt planar polarity phenotype, suggesting that HNT functions to downregulate JUN kinase (JNK) signaling during the establishment of ommatidial planar polarity. HNT expression continues in the photoreceptor cells of the pupal retina. When an ommatidium contains four or more hnt mutant photoreceptor cells, both genetically mutant and genetically wild-type photoreceptor cells fall out of the retinal epithelium, indicating a role for HNT in maintenance of epithelial integrity. In the late pupal stages, HNT regulates the morphogenesis of rhabdomeres within individual photoreceptor cells and the separation of the rhabdomeres of adjacent photoreceptor cells. Apical F-actin is depleted in hnt mutant photoreceptor cells before the observed defects in cellular morphogenesis and epithelial integrity. The analyses presented here, together with our previous studies in the embryonic amnioserosa and tracheal system, show that HNT has a general role in regulation of the F-actin-based cytoskeleton, JNK signaling, cell morphology and epithelial integrity during development.

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