Microglia-Mediated IGF-I Neuroprotection in the<i>rd10</i>Mouse Model of Retinitis Pigmentosa

Arroba, Ana I.; Álvarez-Lindo, Noemí; Rooijen, Nico van; Rosa, Enrique J. de la

doi:10.1167/iovs.11-7736

Cited by 76 publications

(84 citation statements)

References 48 publications

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“…It is well known that the microglia reside predominantly in the IPL and OPL and migrate toward the subretinal space under such disease conditions as retinitis pigmentosa (18)(19)(20)(21). In the DKO mice, increased numbers of Iba1-positive cells were observed in the ONLs, indicating microglial activation (SI Appendix, Fig.…”

Section: Depletion Of Mir-183/96 Leads To Abolished Photopic Erg Respmentioning

confidence: 94%

miR-183/96 plays a pivotal regulatory role in mouse photoreceptor maturation and maintenance

Xiang

Chen

et al. 2017

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

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MicroRNAs (miRNAs) are known to be essential for retinal maturation and functionality; however, the role of the most abundant miRNAs, the miR-183/96/182 cluster (miR-183 cluster), in photoreceptor cells remains unclear. Here we demonstrate that ablation of two components of the miR-183 cluster, miR-183 and miR-96, significantly affects photoreceptor maturation and maintenance in mice. Morphologically, early-onset dislocated cone nuclei, shortened outer segments and thinned outer nuclear layers are observed in the miR-183/96 double-knockout (DKO) mice. Abnormal photoreceptor responses, including abolished photopic electroretinography (ERG) responses and compromised scotopic ERG responses, reflect the functional changes in the degenerated retina. We further identify Slc6a6 as the cotarget of miR-183 and miR-96. The expression level of Slc6a6 is significantly higher in the DKO mice than in the wild-type mice. In contrast, Slc6a6 is down-regulated by adenoassociated virus-mediated overexpression of either miR-183 or miR-96 in wild-type mice. Remarkably, both silencing and overexpression of Slc6a6 in the retina are detrimental to the electrophysiological activity of the photoreceptors in response to dim light stimuli. We demonstrate that miR-183/96-mediated fine-tuning of Slc6a6 expression is indispensable for photoreceptor maturation and maintenance, thereby providing insight into the epigenetic regulation of photoreceptors in mice.miR-183/96/182 cluster | regulation | photoreceptor | taurine transporter | degeneration M icroRNAs (miRNAs) are known to act as important epigenetic coordinators during posttranscriptional processing via the regulation of hundreds of target genes with great temporal and spatial precision (1-3). Wholesale and individual disruption of miRNAs has been shown to result in various retinal defects and other sensorial diseases (4-6). The retinal photoreceptor is a type of ciliated neuron in which the miR-183 cluster represents the most highly expressed miRNAs. Although different mouse models have been generated to determine the roles of the miR-183 cluster, many previous studies have used nonspecific or incomplete miRNA depletion to examine the effects of eliminating specific miRNAs on photoreceptor degeneration (5, 6). Little is known about the impact of a "null" miR-183/96/182 model in vivo.A recent study of miR-182 and miR-183 identified these two miRNAs as essential for the maturation and function of cone photoreceptors (7). In addition, their expression is necessary and sufficient for the formation of cone outer segments (OSs) (7). Another study likewise showed that inactivation of the miR-183 cluster by gene trapping resulted in abnormal electroretinography (ERG) responses, progressive synaptic defects, and progressive retinal degeneration (4). Other investigators have reported that impairment of miR-96 resulted in hair cell death in the inner ear, as well as progressive hearing loss in zebrafish, mice, and humans (8-10). Notwithstanding these findings, however, our understanding of the re...

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Section: Depletion Of Mir-183/96 Leads To Abolished Photopic Erg Respmentioning

confidence: 94%

miR-183/96 plays a pivotal regulatory role in mouse photoreceptor maturation and maintenance

Xiang

Chen

et al. 2017

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

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“…The current literature presents a two-sided story on the role of microglia in disease states. Microglia appear to play beneficial as well as detrimental roles during retinal degeneration (Arroba et al, 2011;Langmann 2007), which likely depends on the severity of the insult (Lai and Todd 2008).…”

Section: Microgliamentioning

confidence: 99%

“…In the rd10 retina, depletion of microglial progenitor cells accelerates photoreceptor death (Sasahara et al, 2008), whilst depleting resident microglia attenuates insulin-like growth factor 1-mediated photoreceptor protection (Arroba et al, 2011).…”

Section: Microgliamentioning

confidence: 99%

Alterations to retinal architecture prior to photoreceptor loss in a mouse model of retinitis pigmentosa

Roche

Wyse-Jackson²,

Byrne³

et al. 2016

Int. J. Dev. Biol.

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Mouse models of retinitis pigmentosa (RP) are essential tools in the pursuit to understand fully what cell types and processes underlie the degeneration observed in RP. Knowledge of these processes is required if we are to develop successful therapies to treat this currently incurable disease. We have used the rd10 mouse model of RP to study retinal morphology prior to photoreceptor loss, using immunohistochemistry and confocal microscopy on cryosections, since little is known about how the mutation affects the retina during this period. We report novel findings that the mutation in the rd10 mouse results in retinal abnormalities earlier than was previously thought. Defects in rod and cone outer segments, bipolar cells, amacrine cells and photoreceptor synapses were apparent in the retina during early stages of postnatal retinal development and prior to the loss of photoreceptors. Additionally, we observed a dramatic response of glial cells during this period. Microglia responded as early as postnatal day (P) 5; ~13 days before any photoreceptor loss is detected with Müller glia and astrocytes exhibiting changes from P10 and P15 respectively. Overall, these findings present pathological aspects to the postnatal development of the rd10 retina, contributing significantly to our understanding of disease onset and progression in the rd10 mouse and provide a valuable resource for the study of retinal dystrophies.

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“…Ex vivo retinal explants and cryosections were performed as previously described [6]. Briefly, postnatal day 23 (P23) rd10 mice were euthanized and their eyes enucleated.…”

Section: Ex Vivo Retinal Explantsmentioning

confidence: 99%

“…We previously reported that proinsulin treatment delays photoreceptor cell death and prolongs visual function in the rd10 mouse [5]. IGF-I also reduces photoreceptor cell death in the rd10 mouse retina, an effect mediated by microglia [6]. In the central nervous system, including the neuroretina, microglia are derived from the macrophage/monocyte lineage.…”

Section: Introductionmentioning

confidence: 99%

Microglia-Müller Glia Crosstalk in the rd10 Mouse Model of Retinitis Pigmentosa

Arroba

Álvarez-Lindo

Rooijen³

et al. 2014

Retinal Degenerative Diseases

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Retinitis pigmentosa refers to a large, genetically heterogeneous group of retinal dystrophies. This condition is characterized by the gradual onset of blindness due to progressive deterioration of the retina, a process that includes photoreceptor and retinal-pigmented-epithelium cell decay and death, microglial recruitment, reactive gliosis, and vascular disorganization and regression. We found that early in the degenerative process, the rd10 mouse retina exhibits high levels of photoreceptor cell death and reactive Müller gliosis. In explant cultures, both degenerative processes were abrogated by IGF-I treatment. Moreover, the beneficial effect of IGF-I was diminished by microglial depletion using clodronate-containing liposomes. Interestingly, in the absence of IGF-I, microglial depletion partially prevented cell death without affecting Müller gliosis. These findings strongly suggest a role for microglia-Müller glia crosstalk in neuroprotection. However, a subpopulation of microglial cells appears to promote neurodegeneration in the dystrophic retina. Our findings indicate that beneficial neuroprotective effects may be achieved through strategies that modulate microglial cell responses.

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Microglia-Mediated IGF-I Neuroprotection in therd10Mouse Model of Retinitis Pigmentosa

Abstract: IGF-I is able to attenuate photoreceptor cell death both ex vivo and in vivo in the rd10 mouse retina. Microglia is required for the neuroprotective effect of IGF-I in the dystrophic retina. In addition, microglial cells play a detrimental role, seemingly led to neuroprotection by IGF-I.

Cited by 76 publications

References 48 publications

miR-183/96 plays a pivotal regulatory role in mouse photoreceptor maturation and maintenance

miR-183/96 plays a pivotal regulatory role in mouse photoreceptor maturation and maintenance

Alterations to retinal architecture prior to photoreceptor loss in a mouse model of retinitis pigmentosa

Microglia-Müller Glia Crosstalk in the rd10 Mouse Model of Retinitis Pigmentosa

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