DICER1 is essential for survival of postmitotic rod photoreceptor cells in mice

Sundermeier, Thomas R.; Zhang, Ning; Vinberg, Frans; Mustafi, Debarshi; Kohno, Hideo; Golczak, Marcin; Bai, Xiaodong; Maeda, Akiko; Kefalov, Vladimir J.; Palczewski, Krzysztof

doi:10.1096/fj.14-254292

Cited by 54 publications

(69 citation statements)

References 53 publications

(88 reference statements)

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“…Dicer1 flox/flox (39) and Dgcr8 flox/flox (38) mice were purchased from Jackson Laboratory (Bar Harbor, ME). Inducible pVMAD2-rtTA-TRE-Cre (40) Morphological and Functional Studies-SD-OCT was performed as described previously (19). For quantification, ONL thickness measurements were made 0.45 mm from the optic nerve head in the nasal, temporal, inferior, and superior direction of each eye, for a total of eight measurements per mouse.…”

Section: Methodsmentioning

confidence: 99%

“…For histology, mice were euthanized by CO 2 asphyxiation, and their eyes were removed and fixed for 48 h at room temperature in Hartmann's fixative (Sigma-Aldrich). Tissue processing, paraffin embedding, immunostaining, and quantification were performed as noted previously (19). For lower magnification images, 24-bit color images were captured at ϫ20 with an Olympus BX-60 upright microscope attached to a Retiga EXi camera (QImaging, Surrey, Canada).…”

Section: Methodsmentioning

confidence: 99%

“…Unsurprisingly, studies on the functional roles of miRNAs in retinal photoreceptors have firmly established that miRNAs are essential for the survival and function of these perpetually stressed post-mitotic cells (19 -24). Conditional knock-out of the miRNA biogenesis factor Dicer1 specifically in mature rods led to progressive retinal degeneration in mice (19). Similarly, the absence of Dgcr8 in post-mitotic cone photoreceptors caused loss of their outer segments (OSs) and deterioration of light responses (20).…”

Section: Dicer1mentioning

confidence: 99%

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MicroRNA-processing Enzymes Are Essential for Survival and Function of Mature Retinal Pigmented Epithelial Cells in Mice

Sundermeier¹,

Sakami²,

Sahu

et al. 2017

Journal of Biological Chemistry

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Edited by Paul E. FraserAge-related macular degeneration (AMD) is a major cause of irreversible vision loss. The neovascular or "wet" form of AMD can be treated to varying degrees with anti-angiogenic drugs, but geographic atrophy (GA) is an advanced stage of the more prevalent "dry" form of AMD for which there is no effective treatment. Development of GA has been linked to loss of the microRNA (miRNA)-processing enzyme DICER1 in the mature retinal pigmented epithelium (RPE). This loss results in the accumulation of toxic transcripts of Alu transposable elements, which activate the NLRP3 inflammasome and additional downstream pathways that compromise the integrity and function of the RPE. However, it remains unclear whether the loss of miRNA processing and subsequent gene regulation in the RPE due to DICER1 deficiency also contributes to RPE cell death. To clarify the role of miRNAs in RPE cells, we used two different mature RPE cell-specific Cre recombinase drivers to inactivate either Dicer1 or DiGeorge syndrome critical region 8 (Dgcr8), thus removing RPE miRNA regulatory activity in mice by disrupting two independent and essential steps of miRNA biogenesis. In contrast with prior studies, we found that the loss of each factor independently led to strikingly similar defects in the survival and function of the RPE and retina. These results suggest that the loss of miRNAs also contributes to RPE cell death and loss of visual function and could affect the pathology of dry AMD. Age-related macular degeneration (AMD)3 is a progressive retinal degenerative disorder that preferentially impacts the macula, the central region of the retina primarily responsible for both color vision and visual acuity. AMD is the leading cause of irreversible vision loss in modern Western societies among adults over 50 and is projected to impact the lives of nearly 200 million people worldwide by the year 2020 (1-4). It presents in two distinct forms, based on the types of lesions that occur in the late stages. The neovascular or "wet" form of AMD is associated with abnormal growth of blood vessels in the choriocapillaris, which extend through Bruch's membrane and cause acute vision loss that can be reversed relatively rapidly through intravitreal injection of vascular endothelial growth factor (VEGF) inhibitors (5-8). In contrast, the dry form of AMD is characterized by a large number of drusen and occasionally by geographic atrophy (GA), the regional loss of macular photoreceptors, retinal pigmented epithelium (RPE), and choriocapillaris. These changes cause deficits in dark adaptation, along with dense visual field scotomas and a gradual decline in visual acuity (9 -11). Currently, there is no effective treatment for the dry form of AMD.Discovered over 2 decades ago in Caenorhabditis elegans, miRNAs regulate gene expression at the post-transcriptional level (12, 13). miRNA biogenesis involves two sequential cleavage steps. The first is accomplished in the nucleus by the microprocessor complex and involves a member of the ribonucleas...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Dicer1mentioning

confidence: 99%

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MicroRNA-processing Enzymes Are Essential for Survival and Function of Mature Retinal Pigmented Epithelial Cells in Mice

Sundermeier¹,

Sakami²,

Sahu

et al. 2017

Journal of Biological Chemistry

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“…Transretinal recordings were performed with isolated mouse retina as previously described (49,50). The isolated retina was carefully mounted on a custom-made chamber for transretinal voltage recordings (51).…”

Section: Rpe65mentioning

confidence: 99%

CRALBP supports the mammalian retinal visual cycle and cone vision

et al. 2015

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“…In silico , RT-PCR and in situ hybridization studies have revealed spatio-temporal expression of miRNAs in the developing and mature retina (Arora et al, 2010; Deo et al, 2006; Hackler et al, 2010; Karali et al, 2010; Ryan et al, 2006; Xu, 2009). In addition, miRNAs exhibit altered expression during circadian cycle (Krol et al, 2010; Xu et al, 2007), cell survival (Damiani et al, 2008; Lumayag et al, 2013; Sundermeier et al, 2014), and in disease conditions (Loscher et al, 2008; Shen et al, 2008). The effect of miRNAs at the intersection of several GRN is exemplified by the “miR-96, miR-182 and miR-183” cluster, which contributes to circadian regulation of gene expression in the retina and has a more general role in neurosensory cell-specific GRNs (Xu et al, 2007).…”

Section: System-level Analysis Of Retinal Photoreceptor Developmentmentioning

confidence: 99%

Vision from next generation sequencing: Multi-dimensional genome-wide analysis for producing gene regulatory networks underlying retinal development, aging and disease

Yang

Ratnapriya

Cogliati

et al. 2015

Progress in Retinal and Eye Research

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Genomics and genetics have invaded all aspects of biology and medicine, opening uncharted territory for scientific exploration. The definition of “gene” itself has become ambiguous, and the central dogma is continuously being revised and expanded. Computational biology and computational medicine are no longer intellectual domains of the chosen few. Next generation sequencing (NGS) technology, together with novel methods of pattern recognition and network analyses, has revolutionized the way we think about fundamental biological mechanisms and cellular pathways. In this review, we discuss NGS-based genome-wide approaches that can provide deeper insights into retinal development, aging and disease pathogenesis. We first focus on gene regulatory networks (GRNs) that govern the differentiation of retinal photoreceptors and modulate adaptive response during aging. Then, we discuss NGS technology in the context of retinal disease and develop a vision for therapies based on network biology. We should emphasize that basic strategies for network construction and analyses can be transported to any tissue or cell type. We believe that specific and uniform guidelines are required for generation of genome, transcriptome and epigenome data to facilitate comparative analysis and integration of multi-dimensional data sets, and for constructing networks underlying complex biological processes. As cellular homeostasis and organismal survival are dependent on gene-gene and gene-environment interactions, we believe that network-based biology will provide the foundation for deciphering disease mechanisms and discovering novel drug targets for retinal neurodegenerative diseases.

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DICER1 is essential for survival of postmitotic rod photoreceptor cells in mice

Cited by 54 publications

References 53 publications

MicroRNA-processing Enzymes Are Essential for Survival and Function of Mature Retinal Pigmented Epithelial Cells in Mice

MicroRNA-processing Enzymes Are Essential for Survival and Function of Mature Retinal Pigmented Epithelial Cells in Mice

CRALBP supports the mammalian retinal visual cycle and cone vision

Vision from next generation sequencing: Multi-dimensional genome-wide analysis for producing gene regulatory networks underlying retinal development, aging and disease

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