Rapid and Integrative Discovery of Retina Regulatory Molecules

Albrecht, Nicholas E.; Alevy, Jonathan; Jiang, Danye; Burger, Courtney A.; Liu, Brian I.; Li, Fenge; Wang, Julia; Kim, Seon‐Young; Hsu, Chih-Wei; Kalaga, Sowmya; Udensi, Uchechukwu; Asomugha, Chinwe; Bohat, Ritu; Gaspero, Angelina; Justice, Monica J.; Westenskow, Peter D.; Yamamoto, Shinya; Seavitt, John R.; Beaudet, Arthur L.; Dickinson, Mary E.; Samuel, Melanie A.

doi:10.1016/j.celrep.2018.07.090

Cited by 15 publications

(15 citation statements)

References 50 publications

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“…Due to the laminar targeting of distinct neuron types in this system (Figure b), neuron‐specific gene expression can be inferred directly from laminar staining. To begin, we obtained adult retinas from 92 BCM KOMP2 center lines (Albrecht et al, ) and stained them for lacZ. We then identified those that displayed differential expression between laminae or between neurons within a lamina (Figure c,d).…”

Section: Resultsmentioning

confidence: 99%

Spatiotemporal gene expression patterns reveal molecular relatedness between retinal laminae

Jiang

Burger

Casasent

et al. 2019

J of Comparative Neurology

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In several areas of the central nervous system, neurons are regionally organized into groups or layers that carry out specific activities. In this form of patterning, neurons of distinct types localize their cell bodies to just one or a few of the layers within a structure. However, little is known about whether diverse neuron types within a lamina share molecular features that coordinate their organization. To begin to identify such candidates, we used the laminated murine retina to screen 92 lacZ reporter lines available through the Knockout Mouse Project. Thirty‐two of these displayed reporter expression in restricted subsets of inner retina neurons. We then identified the spatiotemporal expression patterns of these genes at key developmental stages. This uncovered several that were heavily enriched in development but reduced in adulthood, including the transcriptional regulator Hmga1. An additional set of genes displayed maturation associated laminar enrichment. Among these, we identified Bbox1 as a novel gene that specifically labels all neurons in the ganglion cell layer but is largely excluded from otherwise molecularly similar neurons in the inner retina. Finally, we established Dbn1 as a new marker enriched in amacrines and Fmnl3 as a marker for subsets of αRGCs. Together, these data provide a spatiotemporal map for laminae‐specific molecules and suggest that diverse neuron types within a lamina share coordinating molecular features that may inform their fate or function.

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Section: Resultsmentioning

confidence: 99%

Spatiotemporal gene expression patterns reveal molecular relatedness between retinal laminae

Jiang

Burger

Casasent

et al. 2019

J of Comparative Neurology

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“…These gene signatures potentially point to cellular physiological processes influenced by CNTF to enhance neuronal viability. RNA-seq analyses may also capture novel retinal regulatory genes 27 . A recent study of retinal transcriptomes from ~500 age-related macular degeneration (AMD) cases identified ~50 AMD genes 44 .…”

Section: Discussionmentioning

confidence: 99%

“…6a). In addition, we detected signatures that overlapped between CNTF-dependent genes and retina regulatory genes 27 (Fig. 6a).…”

Section: Commonality Of Retinal Transcriptome Changes Among Degeneratmentioning

confidence: 99%

Impacts of ciliary neurotrophic factor on the retinal transcriptome in a mouse model of photoreceptor degeneration

Wang

Rhee

Pellegrini

et al. 2020

Sci Rep

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ciliary neurotrophic factor (cntf) has been tested in clinical trials for human retinal degeneration due to its potent neuroprotective effects in various animal models. To decipher CNTF-triggered molecular events in the degenerating retina, we performed high-throughput RnA sequencing analyses using the Rds/Prph2 (P216L) transgenic mouse as a preclinical model for retinitis pigmentosa. In the absence of cntf treatment, transcriptome alterations were detected at the onset of rod degeneration compared with wild type mice, including reduction of key photoreceptor transcription factors Crx, Nrl, and rod phototransduction genes. Short-term CNTF treatments caused further declines of photoreceptor transcription factors accompanied by marked decreases of both rod-and cone-specific gene expression. in addition, cntf triggered acute elevation of transcripts in the innate immune system and growth factor signaling. These immune responses were sustained after long-term CNTF exposures that also affected neuronal transmission and metabolism. Comparisons of transcriptomes also uncovered common pathways shared with other retinal degeneration models. Cross referencing bulk RNA-seq with single-cell RnA-seq data revealed the cntf responsive cell types, including Müller glia, rod and cone photoreceptors, and bipolar cells. Together, these results demonstrate the influence of exogenous cntf on the retinal transcriptome landscape and illuminate likely cntf impacts in degenerating human retinas. Retinal degeneration (RD) is known as an irreversible, progressive neurologic disorder caused by genetic mutations and/or environmental or pathological damage to the retina. One therapeutic strategy to attenuate vision loss in disease conditions is treating the retina with neuroprotective agents that promote neuronal viability. Ciliary neurotrophic factor (CNTF) has been shown to be a potent neuroprotective agent for various types of retinal degenerations, including those caused by gene mutations, light-induced damage, and physical injury 1. Since CNTF enhances the survival of both photoreceptors and retinal ganglion cells, the two major cell classes damaged in retinal degenerative diseases, a CNTF-based therapy has been developed and tested in several clinical trials. To date, outcomes of the trials for retinitis pigmentosa, geographic atrophy, and achromatopsia have not demonstrated sufficient therapeutic benefits for human patients 2-5. However, CNTF therapy for macular telangiectasia type 2 has shown efficacy 6,7 , and a clinical trial for the second largest blinding disease glaucoma 8 is ongoing (https://clinicaltrials.gov/ct2/show/NCT01408472). To shed light on the molecular and cellular mechanisms of CNTF-mediated neuroprotection, we have delivered the same secreted recombinant CNTF used in human trials to a mouse model expressing the Rds/peripherin2 (Prph2) transgene with the P216L mutation 9. Pheripherin2 is a structural protein of the photoreceptor outer segment disc, and over 80 PRPH2 pathological mutations have been linked to RD, with...

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“…We performed ERG on adult 16 week-old animals controls as previously described (Albrecht et al, 2018). In brief, mice (n = 7 mutants and 8 wildtype) were dark adapted overnight and anesthetized with 1.5% isoflurane at an oxygen flow rate of 1.0 L/min.…”

Section: Ergmentioning

confidence: 99%

“…Given these features, we recently established a pipeline for using mouse retina to identify new regulators of neurons, vasculature, and their interactions (Albrecht et al, 2018). This screen implicated several novel genes in retinal vasculature organization, including the potassium channel tetramerization domain-containing protein 7 (Kctd7).…”

Section: Introductionmentioning

confidence: 99%

Progressive myoclonic epilepsy-associated geneKctd7regulates retinal neurovascular patterning and function

Alevy

Burger

Albrecht

et al. 2019

Preprint

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Rapid and Integrative Discovery of Retina Regulatory Molecules

Cited by 15 publications

References 50 publications

Spatiotemporal gene expression patterns reveal molecular relatedness between retinal laminae

Spatiotemporal gene expression patterns reveal molecular relatedness between retinal laminae

Impacts of ciliary neurotrophic factor on the retinal transcriptome in a mouse model of photoreceptor degeneration

Progressive myoclonic epilepsy-associated geneKctd7regulates retinal neurovascular patterning and function

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