cGMP Accumulation Causes Photoreceptor Degeneration in CNG Channel Deficiency: Evidence of cGMP Cytotoxicity Independently of Enhanced CNG Channel Function

Xu, Jianhua; Morris, Lilah F.; Thapa, Arjun; Ma, Hongwei; Michalakis, Stylianos; Biel, Martin; Baehr, Wolfgang; Peshenko, Igor V.; Dizhoor, Alexander M.; Ding, Xi

doi:10.1523/jneurosci.0909-13.2013

Cited by 63 publications

(90 citation statements)

References 40 publications

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“…When RetGC1 deceleration by Ca 2ϩ in the dark becomes less sensitive, a larger fraction of cGMP-gated channels in the plasma membrane maintains Ca 2ϩ influx in the dark, eventually provoking the onset of apoptosis (62,63). Stimulation of cGMP-dependent protein kinase activity can also lead to mouse photoreceptor death independently of the Ca 2ϩ pathway (64,65). In our present study, faster rod degeneration accompanied a larger shift in Ca 2ϩ sensitivity of the cGMP synthesis in the retina (Fig.…”

Section: What Processes Downstream Of the Mutated Cord6 Retgc1 Cause supporting

confidence: 54%

The R838S Mutation in Retinal Guanylyl Cyclase 1 (RetGC1) Alters Calcium Sensitivity of cGMP Synthesis in the Retina and Causes Blindness in Transgenic Mice

Dizhoor

Peshenko

2016

Journal of Biological Chemistry

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Edited by Roger ColbranSubstitutions of Arg 838 in the dimerization domain of a human retinal membrane guanylyl cyclase 1 (RetGC1) linked to autosomal dominant cone-rod degeneration type 6 (CORD6) change RetGC1 regulation in vitro by Ca 2؉ . In addition, we find that R838S substitution makes RetGC1 less sensitive to inhibition by retinal degeneration-3 protein (RD3). We selectively expressed human R838S RetGC1 in mouse rods and documented the decline in rod vision and rod survival. To verify that changes in rods were specifically caused by the CORD6 mutation, we used for comparison cones, which in the same mice did not express R838S RetGC1 from the transgenic construct. The R838S RetGC1 expression in rod outer segments reduced inhibition of cGMP production in the transgenic mouse retinas at the free calcium concentrations typical for dark-adapted rods. The transgenic mice demonstrated early-onset and rapidly progressed with age decline in visual responses from the targeted rods, in contrast to the longer lasting preservation of function in the non-targeted cones. The decline in rod function in the retina resulted from a progressive degeneration of rods between 1 and 6 months of age, with the severity and pace of the degeneration consistent with the extent to which the Ca 2؉ sensitivity of the retinal cGMP production was affected. Our study presents a new experimental model for exploring cellular mechanisms of the CORD6-related photoreceptor death. This mouse model provides the first direct biochemical and physiological in vivo evidence for the Arg 838 substitutions in RetGC1 being the culprit behind the pathogenesis of the CORD6 congenital blindness.Retinal membrane guanylyl cyclase (RetGC) 2 is one of the key enzymes in vertebrate visual signaling. Rods and cones respond to light by closing cGMP-gated plasma membrane channels in the outer segment as cGMP becomes hydrolyzed by phosphodiesterase PDE6 and then re-open the channels, after PDE6 activity becomes quenched and cGMP becomes re-synthesized by RetGC (1-5). Two RetGC isozymes expressed in photoreceptors, , bind calcium-sensor proteins, GCAPs (7-12), which decelerate the cyclase activity at high intracellular calcium concentrations in the dark and accelerate it in the light, when the influx of calcium through the cGMP-gated channels is shut off (13)(14)(15)(16)(17)(18)(19). RetGC also binds retinal degeneration 3 (RD3) protein (20 -21), which prevents cyclase activation by GCAPs (22-23) and promotes accumulation of RetGC1 in the outer segments (21,24,25). RetGC1 (human gene GUCY2D) accounts for most of the cGMP synthesis in mammalian photoreceptors (26,27), therefore mutations in RetGC1 that disable the cyclase activity (28 -33) cause recessive blindness at birth, Leber congenital amaurosis type 1 (LCA1) (33), mostly a non-degenerative or partially degenerative (31, 32) loss-of-function hereditary retinal disease. Different from the LCA1 type of severe congenital blindness linked to the RetGC1 gene, cone-rod dystrophy type 6 (CORD6), is a progressive ear...

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Section: What Processes Downstream Of the Mutated Cord6 Retgc1 Cause supporting

confidence: 54%

The R838S Mutation in Retinal Guanylyl Cyclase 1 (RetGC1) Alters Calcium Sensitivity of cGMP Synthesis in the Retina and Causes Blindness in Transgenic Mice

Dizhoor

Peshenko

2016

Journal of Biological Chemistry

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“…These results support a recent report showing that PKG was increased in a mouse model of retinal degeneration. 28 In addition, as Rip3 is known to be induced by tumor necrosis factor a (TNFa), 29 we examined the spatiotemporal expression pattern of TNFa in mutant pde6c w59 retina. TNFa expression began at 3 d.p.f.…”

Section: Resultsmentioning

confidence: 99%

Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish

et al. 2014

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Achromatopsia is a progressive autosomal recessive retinal disease characterized by early loss of cone photoreceptors and later rod photoreceptor loss. In most cases, mutations have been identified in CNGA3, CNGB3, GNAT2, PDE6C or PDE6H genes. Owing to this genetic heterogeneity, mutation-independent therapeutic schemes aimed at preventing cone cell death are very attractive treatment strategies. In pde6c w59 mutant zebrafish, cone photoreceptors expressed high levels of receptor-interacting protein kinase 1 (RIP1) and receptor-interacting protein kinase 3 (RIP3) kinases, key regulators of necroptotic cell death. In contrast, rod photoreceptor cells were alternatively immunopositive for caspase-3 indicating activation of caspase-dependent apoptosis in these cells. Morpholino gene knockdown of rip3 in pde6c w59 embryos rescued the dying cone photoreceptors by inhibiting the formation of reactive oxygen species and by inhibiting second-order neuron remodelling in the inner retina. In rip3 morphant larvae, visual function was restored in the cones by upregulation of the rod phosphodiesterase genes (pde6a and pde6b), compensating for the lack of cone pde6c suggesting that cones are able to adapt to their local environment. Furthermore, we demonstrated through pharmacological inhibition of RIP1 and RIP3 activity that cone cell death was also delayed.Collectively, these results demonstrate that the underlying mechanism of cone cell death in the pde6c w59 mutant retina is through necroptosis, whereas rod photoreceptor bystander death occurs through a caspase-dependent mechanism. This suggests that targeting the RIP kinase signalling pathway could be an effective therapeutic intervention in retinal degeneration patients. As bystander cell death is an important feature of many retinal diseases, combinatorial approaches targeting different cell death pathways may evolve as an important general principle in treatment.

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“…The cGMP-gated Cnga3 regulates cationic influx in cones, and Pde6 cleaves intracellular cGMP in response to phototransduction activation. Loss-of-function mutation in either Cnga3 or Pde6c led to intracellular accumulation of cGMP, which was linked to photoreceptor death (45,46). Whereas it is not known whether changes in intracellular cGMP levels in cones in either mutant played a role in the development of late-phase NT deficiency, it is conceivable that cGMP, an important second messenger, can impact many cellular homeostatic processes.…”

Section: Discussionmentioning

confidence: 99%

Maturation arrest in early postnatal sensory receptors by deletion of the miR-183/96/182 cluster in mouse

Fan

et al. 2017

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

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The polycistronic miR-183/96/182 cluster is preferentially and abundantly expressed in terminally differentiating sensory epithelia. To clarify its roles in the terminal differentiation of sensory receptors in vivo, we deleted the entire gene cluster in mouse germline through homologous recombination. The miR-183/96/ 182 null mice display impairment of the visual, auditory, vestibular, and olfactory systems, attributable to profound defects in sensory receptor terminal differentiation. Maturation of sensory receptor precursors is delayed, and they never attain a fully differentiated state. In the retina, delay in up-regulation of key photoreceptor genes underlies delayed outer segment elongation and possibly mispositioning of cone nuclei in the retina. Incomplete maturation of photoreceptors is followed shortly afterward by early-onset degeneration. Cell biologic and transcriptome analyses implicate dysregulation of ciliogenesis, nuclear translocation, and an epigenetic mechanism that may control timing of terminal differentiation in developing photoreceptors. In both the organ of Corti and the vestibular organ, impaired terminal differentiation manifests as immature stereocilia and kinocilia on the apical surface of hair cells. Our study thus establishes a dedicated role of the miR-183/96/182 cluster in driving the terminal differentiation of multiple sensory receptor cells. M ammalian sensory epithelia, such as those underlying vison, hearing, smell, and balance, consist of ciliated sensory receptor cells. Although highly specialized, similarities in embryonic origin underlie common features in their development (1). Following specification, lineage-restricted postmitotic precursors become structurally and functionally mature through a series of cellular differentiation events, collectively described as terminal differentiation (2). During maturation, sensory receptor cells typically develop microtubule-based primary cilia and in some cases actin-based membrane protrusions on apical membranes, which are sensory organelles, while maintaining apical basal polarity within sensory epithelia. In photoreceptors, for example, the extension of outer segments (OSs), specialized sensory cilia, is central to postmitotic differentiation and necessary for light sensitivity (3). In auditory and vestibular hair cells, the proper formation of hair bundles is indispensable for detecting sound and head positions (4). Similarly, olfactory sensory neurons (OSNs), the odorant receptor cells in the olfactory epithelium, project multiple dendritic cilia into the mucous membrane of the nasal epithelium where olfactory signaling is initiated (5). Mature sensory epithelia are highly structured with specific spatial organization that is tied to their functions. Synchronized planar cell polarity (PCP) of hair cells in the inner ear, for example, provides their directional sensitivity (6), whereas the development of laminar architecture in the retina restricts photoreceptors to proper compartments for efficient wiring with secondary neuro...

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cGMP Accumulation Causes Photoreceptor Degeneration in CNG Channel Deficiency: Evidence of cGMP Cytotoxicity Independently of Enhanced CNG Channel Function

Cited by 63 publications

References 40 publications

The R838S Mutation in Retinal Guanylyl Cyclase 1 (RetGC1) Alters Calcium Sensitivity of cGMP Synthesis in the Retina and Causes Blindness in Transgenic Mice

The R838S Mutation in Retinal Guanylyl Cyclase 1 (RetGC1) Alters Calcium Sensitivity of cGMP Synthesis in the Retina and Causes Blindness in Transgenic Mice

Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish

Maturation arrest in early postnatal sensory receptors by deletion of the miR-183/96/182 cluster in mouse

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