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PTEN inhibition dedifferentiates long-distance axon-regenerating intrinsically photosensitive retinal ganglion cells and upregulates mitochondria-associated DYNLT1A and LARS2

ABSTRACT: PTEN inhibition dedifferentiates long-distance axon-regenerating intrinsically photosensitive retinal ganglion cells and upregulates mitochondria-associated DYNLT1A and LARS2

PROVIDER: PRJNA864030 | ENA |

REPOSITORIES: ENA

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PTEN inhibition dedifferentiates long-distance axon-regenerating intrinsically photosensitive retinal ganglion cells and upregulates mitochondria-associated DYNLT1A and LARS2

Project description:The central nervous system (CNS) projection neurons fail to spontaneously regenerate injured axons. Targeting the developmentally regulated genes in order to reactivate embryonic intrinsic axon growth capacity, or targeting tumor suppressor genes such as Pten, promote axon regeneration in a subset of injured retinal ganglion cells (RGCs). The subset of RGCs that regenerate axons in response to inhibition of Pten was narrowed-down to the Opn4+ intrinsically photosensitive (ip) and α subtypes of RGCs. Here, we used single cell RNA-sequencing (scRNA-seq) to investigate why only a subset of injured RGCs regenerate axons in response to Pten knockdown (KD), and to characterize the relationship between axon regeneration promoted by targeting Pten and the developmental decline in intrinsic axon growth capacity. We found that, only the most similar to embryonic state ipRGC subtypes C33 and C40 regenerated axons in response to Pten KD, which dedifferentiated them even further towards an embryonic state. We also found that genes downstream of Pten KD, specifically in the RGCs that regenerated axons, include mitochondria-associated developmentally regulated and non-developmentally regulated Dynlt1a and Lars2, respectively, which promoted axon regeneration on their own. Overall, we show that injury itself reverts transcriptome towards an embryonic state only in some neuronal subtypes and not sufficiently close to embryonic state to confer response to Pten KD, whereas certain mature neuronal subtypes are similar to embryonic state even without injury, which primes them to regenerate axons in response to Pten KD, that dedifferentiates them further towards an embryonic state and upregulates mitochondria-associated Dynlt1a and Lars2.

2023-04-11 | GSE210137 | GEO

Pten inhibition dedifferentiates long-distance axon-regenerating intrinsically photosensitive retinal ganglion cells and upregulates mitochondria-associated Dynlt1a and Lars2.

Project description:Central nervous system projection neurons fail to spontaneously regenerate injured axons. Targeting developmentally regulated genes in order to reactivate embryonic intrinsic axon growth capacity or targeting pro-growth tumor suppressor genes such as Pten promotes long-distance axon regeneration in only a small subset of injured retinal ganglion cells (RGCs), despite many RGCs regenerating short-distance axons. A recent study identified αRGCs as the primary type that regenerates short-distance axons in response to Pten inhibition, but the rare types which regenerate long-distance axons, and cellular features that enable such response, remained unknown. Here, we used a new method for capturing specifically the rare long-distance axon-regenerating RGCs, and also compared their transcriptomes with embryonic RGCs, in order to answer these questions. We found the existence of adult non-α intrinsically photosensitive M1 RGC subtypes that retained features of embryonic cell state, and showed that these subtypes partially dedifferentiated towards an embryonic state and regenerated long-distance axons in response to Pten inhibition. We also identified Pten inhibition-upregulated mitochondria-associated genes, Dynlt1a and Lars2, which promote axon regeneration on their own, and thus present novel therapeutic targets.

| S-EPMC10163351 | biostudies-literature

Transcriptomic Signatures of Postnatal and Adult Intrinsically Photosensitive Ganglion Cells

Project description:Transcriptomic Signatures of Postnatal and Adult Intrinsically Photosensitive Ganglion Cells

| PRJNA486790 | ENA

Single-cell RNAseq data from mouse intrinsically-photosensitive retinal ganglion cells

Project description:Single-cell RNAseq data from mouse intrinsically-photosensitive retinal ganglion cells

| PRJNA931936 | ENA

Transcriptomic Signatures of Postnatal and Adult Intrinsically Photosensitive Ganglion Cells

Project description:Purpose: The goal of this study was to determine a “molecular parts list” for intrinsically photosensitive retinal ganglion cells (ipRGCs), which are rare mammalian photoreceptors essential for non-image-forming vision functions, such as circadian photoentrainment and the pupillary light reflex. Methods: We conducted a thorough unbiased transcriptomic analysis of ipRGCs by purifying GFP-tagged ipRGCs through a combination of FACS and immunoaffinity and comparing this the transcriptional profile of GFP-negative RGCs. We did this in two different mouse lines, marking partially overlapping subsets of ipRGCs. One was a BAC transgenic reporter (Opn4-GFP), which fluorescently labels M1-M3 ipRGCs and the other was a Opn4-Cre;Z/EG reporter system, which labels all ipRGC subtypes, M1-M6 Results: We find dozens of novel genes highly enriched in ipRGCs. We reveal that Rasgrp1 and Tbx20 are selectively expressed in subsets of ipRGCs, though these molecularly defined groups imperfectly match established ipRGC subtypes. We demonstrate that the ipRGCs regulating circadian photoentrainment are unexpectedly diverse at the molecular level. Conclusions: Our study represents the first detailed analysis of ipRGC transcriptomes by RNA-seq. Our findings reveal unexpected complexity in gene expression patterns across mammalian ipRGC subtypes.

2019-08-15 | GSE118780 | GEO

Developmental control of rod photoreceptor number via a light-dependent retrograde pathway from intrinsically photosensitive retinal ganglion cells

Project description:Photoreception, a form of sensory experience, is essential for normal development of the mammalian visual system. Detecting photons during development is a prerequisite for visual system function - from shaping vision’s first synapse and maturation of retinal vascular networks, to transcriptional establishment and maturation of cell types within the visual cortex. Consistent with this theme, we find that the lighting environment regulates developmental rod photoreceptor apoptosis via OPN4-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs). Using a combination of genetics, sensory environment manipulations, and computational approaches, we establish a molecular pathway in which light-dependent glutamate release from ipRGCs is detected via a transiently expressed kainate receptor (GRIK3) in rod precursors localized to the inner retina. Communication between ipRGCs and nascent inner retinal rods appears to be mediated by transient hybrid neurites projecting from ipRGCs that sense light before eye-opening. These structures, previously referred to as outer retinal dendrites (ORDs), span the ipRGC-rod precursor distance over the first postnatal week and contain the machinery for sensory detection (melanopsin, OPN4) and anterograde neurotransmitter release (Synaptophysin and VGLUT2). Computational and histological assessment of human mid-gestation development reveal conservation of several hallmarks of an ipRGC-to-rod precursor pathway, including displaced rod precursors, transient GRIK3 expression in the rod lineage, and the presence of ipRGCs with putative neurites projecting deep into the developing human retina. Thus, this analysis defines a retinal retrograde signaling pathway that links the sensory environment to rod precursors via ipRGC photoreceptors, allowing the visual system to adapt to distinct lighting environments prior to eye-opening.

2024-07-04 | GSE269102 | GEO

Single-cell RNAseq data from mouse intrinsically-photosensitive retinal ganglion cells

Project description:The goal of this study was to characterize the transcriptomes of intrinsically-photosenstive retinal ganglion cells that innervate different retinorecipient target regions in the brain

2023-05-01 | GSE224600 | GEO

The premammillary nucleus (PMM) of the mediobasal hypothalamus: Photosensitive vs. Photorefractory

Project description:Gene expression profiling of the premammillary nucleus comparing short day photosensitive, long day photosensitive, and long day photorefractory turkey hens

2015-03-11 | GSE66713 | GEO

Developmental control of rod photoreceptor number via a light-dependent retrograde pathway from intrinsically photosensitive retinal ganglion cells

Project description:Developmental control of rod photoreceptor number via a light-dependent retrograde pathway from intrinsically photosensitive retinal ganglion cells

| PRJNA1120107 | ENA

Distance Effect

Project description:Here we show that regions of the honeybee brain involved in visual processing and learning and memory show a genomic response to distance information. Using a method that separates effects of perceived distance from effects of actual distance flown, we found that individuals forced to shift from a short to a perceived long distance to reach a feeding site showed differences in gene expression in the optic lobes and mushroom bodies relative to individuals that continued to perceive flying a short distance.

2011-03-05 | E-TABM-910 | biostudies-arrayexpress

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