Development and maintenance of vision’s first synapse

Burger, Courtney A.; Jiang, Danye; Mackin, Robert; Samuel, Melanie A.

doi:10.1016/j.ydbio.2021.04.001

Cited by 32 publications

(22 citation statements)

References 327 publications

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“…Finally, we analyzed cellular maturation through using synaptic markers. 66 We observed significant upregulation of a number of PR and pan-retina associated synaptic genes (e.g. SV2 , SNAP25, SYP, RIMS2 ,etc.…”

Section: Resultsmentioning

confidence: 79%

Timed Notch Inhibition drives Photoreceptor fate specification in Human Retinal Organoids

Chew

Martinez

Chirco

et al. 2022

Preprint

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PurposeTransplanting photoreceptors from human pluripotent stem cell derived retinal organoids have the potential to reverse vision loss in affected individuals. However, transplantable photoreceptors are only a subset of all cells in the organoids. Hence the goal of our current study was to accelerate and synchronize photoreceptor differentiation in retinal organoids by inhibiting the Notch signaling pathway at different developmental time-points using a small molecule, PF-03084014 (PF).MethodsHuman induced pluripotent stem cell (hiPSC)- and embryonic stem cells (hESC)-derived retinal organoids were treated with 10μM PF for three days at day 45 (D45), D60, D90 and D120 of differentiation. Organoids collected at 14-, 28-, and 42-days post-PF treatment were analyzed for progenitor and photoreceptor markers and Notch pathway inhibition by immunohistochemistry (IHC), quantitative PCR (qPCR) and bulk RNA-seq (n=3-5 organoids from 3 independent experiments).ResultsRetinal organoids collected at 14-days post-PF treatment showed a decrease in progenitor markers (KI67, VSX2, PAX6, and LHX2) and an increase in differentiated pan-photoreceptor markers (OTX2, CRX, and RCVRN) at all organoid stages except D120. PF-treated organoids at D45 and D60 exhibited an increase in cone photoreceptor markers (RXRG and ARR3). PF-treatment at D90 revealed an increase in cone and rod photoreceptors markers (ARR3, NRL, and NR2E3). Bulk RNA-seq analysis mirrored the IHC data and qPCR confirmed Notch effector inhibition.ConclusionsTiming the Notch pathway inhibition in human retinal organoids to align with progenitor competency stages can yield an enriched population of early cone or rod photoreceptors.

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Section: Resultsmentioning

confidence: 79%

Timed Notch Inhibition drives Photoreceptor fate specification in Human Retinal Organoids

Chew

Martinez

Chirco

et al. 2022

Preprint

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“…Operating in the similar fashion as that of the brain, the function of the neuronal network of the retina is also dependent on the spatially ordered organization of projection neurons and interneurons as well as their synaptic connections. Photoreceptors form synaptic connections with bipolar cells and horizontal cells, constituting the first information relay point in the visual pathway ( Burger et al, 2021 ). Bipolar cells are the projection neurons in the retina, relaying the information generated in photoreceptors to the third-order retinal ganglion cells, the specialized retinal neurons that send out the vision information to the brain.…”

Section: Discussionmentioning

confidence: 99%

Cuscuta chinensis Lam. Protects Against Light-Induced Retinal Degeneration: Therapeutic Implications for Photoreceptor Degenerative Disorders

Zhu²,

Li³

et al. 2022

Front. Pharmacol.

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Cuscuta chinensis Lam. (CCL) is a medicinal herb widely used in traditional Chinese medicine for the treatment of ophthalmic diseases, including age-dependent vision-threatening retinal degenerative disorders that involve irreversible loss of the first-order retinal neurons, photoreceptors. However, evidence is lacking if CCL is pharmacologically active at protecting against loss of photoreceptors and photoreceptor degeneration-associated retinal structural and functional impairment. The current study thus evaluates the potential photoreceptor protective effects of CCL to better support its clinical applications in the prevention and treatment of photoreceptor degenerative diseases. Non-invasive full-retinal optical coherence tomography, electroretinography, histological examination, immunohistochemistry and real-time qPCR analysis were performed to assess the retinal protective effects of CCL in light-exposed BALB/c mice characterized by photooxidative stress-mediated photoreceptor loss and associated retinal morphological and functional impairment. The results showed that CCL treatment protected against light-induced degeneration of the photoreceptor structure and deterioration of the retinal function. Furthermore, CCL treatment increased the retinal expression of rhodopsin, S-opsin and M-opsin, supporting the protective effects of CCL in both rod and cone photoreceptors. CCL treatment suppressed photoreceptor cell death in the light-exposed retinas. The morphological integrity of the second-order retinal neurons was also preserved as a result of CCL treatment. In addition, CCL treatment attenuated light-induced reactive müller gliosis, microglial activation and inflammation in the retina. In conclusion, the current work demonstrates for the first time that CCL protects against photooxidative stress-mediated degeneration of photoreceptors and associated disturbance of structural, functional and immune homeostasis of the retina. The findings here thus provide novel experimental evidence supporting the clinical application of CCL in the prevention and treatment photoreceptor degenerative diseases.

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“…These results suggest that bipolar subtype birthdates correlate with visual function, and that subtype maturation follows the order of subtype births. Cone bipolar subtypes invaginate cone pedicles before RBPs invaginate rod spherules (reviewed in [35]), and the OFF sublaminae of the IPL matures before the ON sublamiae [36]. These observations suggest that the time of birth and maturation of bipolar subtypes are correlated, but further studies are required to track the process in individual cells.…”

Section: Bipolar Subtypes Birthdates Are Ordered Reflecting Their Functionmentioning

confidence: 99%

Spatiotemporal patterns of neuronal subtype genesis suggest hierarchical development of retinal diversity

West

Lapan

Lee

et al. 2021

Preprint

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How do neuronal subtypes emerge during development? Recent molecular studies have expanded our knowledge of existing neuronal diversity. However, the genesis of neuronal subtypes remains elusive and previous studies have been limited by a lack of quantitative methods for simultaneous detection of subtype diversity in situ. The bipolar interneurons of the mammalian retina represent a diverse neuronal class, characterized by distinct functions, morphologies, and recently discovered transcriptional profiles. Here, we developed a comprehensive spatiotemporal map of bipolar subtype genesis in the retina. Combining multiplexed detection of 16 RNA markers with timed delivery of EdU and BrdU, we analyzed more than 30,000 single cells in full retinal sections to classify all bipolar subtypes and their birthdates. We found that bipolar subtype birthdates are ordered and follow a centrifugal developmental axis. Spatial analysis revealed a striking oscillatory wave pattern of bipolar subtype birthdates, and lineage analyses suggest clonal restriction on homotypic subtype production. These results inspired a hierarchical model of neuronal subtype genesis in the mammalian retina, with the wave pattern of subtype birthdates arising from early asymmetric cell divisions among founding retinal progenitor cells. Our results provide an outline of the developmental logic that generates diverse neuronal subtypes, and establishes a framework for studying subtype diversification.

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Development and maintenance of vision’s first synapse

Cited by 32 publications

References 327 publications

Timed Notch Inhibition drives Photoreceptor fate specification in Human Retinal Organoids

Timed Notch Inhibition drives Photoreceptor fate specification in Human Retinal Organoids

Cuscuta chinensis Lam. Protects Against Light-Induced Retinal Degeneration: Therapeutic Implications for Photoreceptor Degenerative Disorders

Spatiotemporal patterns of neuronal subtype genesis suggest hierarchical development of retinal diversity

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