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Functional Optic Tract Rewiring via Subtype- and Target-specific Axonal Regeneration and Presynaptic Activity Enhancement (scRNA-Seq)

ABSTRACT: Mechanisms underlying functional axonal rewiring after adult mammalian central nervous system (CNS) injuries remain unclear partially due to limited models. Using a mouse intracranial pre–olivary pretectal nucleus (OPN) optic tract injury model, we demonstrate that Pten/Socs3 knockout and CNTF expression in retinal ganglion cells (RGCs) promotes optic tract regeneration and reinnervation into OPN. Revealed by transmission electron microscopy, trans-synaptic labeling and electrophysiology, functional synapses are formed in OPN mainly by intrinsically photosensitive RGCs, thereby partially restoring the pupillary light reflex (PLR). Furthermore, combining with Lipin-1 knockdown accelerates the recovery and achieves functional reconnection in the chronic injury paradigm. PLR can be further boosted by increasing either RGC photosensitivity with melanopsin or optic tract presynaptic release with a voltage-gated calcium channel modulator, the latter of which also improves corticospinal-tract-sprouting-induced functional recovery after stroke. These findings highlight the importance of neuronal types and presynaptic activity for functional reconnection after CNS injuries.

ORGANISM(S): Mus musculus

PROVIDER: GSE267935 | GEO | 2025/01/23

REPOSITORIES: GEO

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Functional Optic Tract Rewiring via Subtype- and Target-specific Axonal Regeneration and Presynaptic Activity Enhancement (bulk RNA-Seq)

Project description:Mechanisms underlying functional axonal rewiring after adult mammalian central nervous system (CNS) injuries remain unclear partially due to limited models. Using a mouse intracranial pre–olivary pretectal nucleus (OPN) optic tract injury model, we demonstrate that Pten/Socs3 knockout and CNTF expression in retinal ganglion cells (RGCs) promotes optic tract regeneration and reinnervation into OPN. Revealed by transmission electron microscopy, trans-synaptic labeling and electrophysiology, functional synapses are formed in OPN mainly by intrinsically photosensitive RGCs, thereby partially restoring the pupillary light reflex (PLR). Furthermore, combining with Lipin-1 knockdown accelerates the recovery and achieves functional reconnection in the chronic injury paradigm. PLR can be further boosted by increasing either RGC photosensitivity with melanopsin or optic tract presynaptic release with a voltage-gated calcium channel modulator, the latter of which also improves corticospinal-tract-sprouting-induced functional recovery after stroke. These findings highlight the importance of neuronal types and presynaptic activity for functional reconnection after CNS injuries.

2025-01-23 | GSE267936 | GEO

Proteomic characteristics in degenerated and regenerative mouse retina

Project description:The retina constitutes a segment of the central nervous system (CNS). Both retinal and CNS neurons lack the inherent capacity to spontaneously regenerate axons following injury. Retinal ganglion cells (RGCs) serve as the neurons connecting the eyes to the brain. Diseases such as glaucoma initiate damage to RGC axons at the optic nerve, ultimately leading to cell death and irreversible vision loss. While enhancing the survival of RGCs is a crucial initial step, especially for those with pre-existing axonal injuries in the optic nerve due to prolonged insults, effective therapies should also promote axon regeneration. Neuro-regeneration and reintegration into the brain remain to be enormous challenges in neurology and ophthalmology. Despite decades of effort and resources invested in the research of neuro-regeneration, scientists are still rather far from comprehensively identifying all intrinsic axonal growth regulators and their collaborative roles. Data-independent acquisition mass spectrometry (DIA-MS) is a next-generation proteomic methodology that generates permanent digital proteome maps offering highly reproducible retrospective analysis of cellular and tissue specimens. Compared to conventional mass-spectrometry, DIA-MS provides better reproducibility and sensitivity. In this study, we employed DIA-MS to conduct a comprehensive protein expression mapping in retinas from mouse models of degeneration and regeneration, and to gain insights into the complex molecular mechanisms associated with degeneration and regeneration processes in the retina.

2024-07-29 | PXD049992 | Pride

Mass spectrometry dataset of LC-MS Lipidomics Analysis of Xenopus Laevis Optic Nerve

Project description:CNS injuries of the anuran amphibian, Xenopus laevis, are uniquely befitted for studying the molecular compositions of neuronal regeneration of retinal ganglion cells (RGC) due to a functional recovery of optic axons disparate to adult mammalian analogues. RGCs and their optic nerve axons undergo irreversible neurodegeneration in glaucoma and associated optic neuropathies, resulting in blindness in mammals. Conversely, Xenopus demonstrates RGC lifetime-spanning regenerative capabilities after optic nerve crush, inciting opportunities to compare de novo regeneration and develop efficient pharmaceutical approaches for vision restoration. Studies revealing lipidome alterations during optic nerve regeneration are sparse and could serve as a solid foundation for these underlying molecular changes. We profile the lipid changes in a transgenic line of 1 year old Xenopus laevis Tg(islet2b:gfp) frogs that were either left untreated (naïve) or had a monocular surgery of either a left optic crush injury (crush) or sham surgery (sham). Matching controls of uninjured right optic nerves were also collected (control). Tg(islet2b:gfp) frogs were allowed to recover for 7,12,18, and 27 days post optic nerve crush. Following euthanasia, the optic nerves were collected for lipidomic analysis. A modified Bligh and Dyer method [PMID: 13671378] was used for lipid extraction, followed by untargeted mass spectrometry lipid profiling with a Q-Exactive Orbitrap Liquid Chromatography-Mass Spectrometer (LC MS-MS) coupled with Vanquish Horizon Binary UHPLC LC-MS system.

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Sustained axon regeneration induced by a synergy of PTEN and SOCS3 deletion

Project description:A formidable challenge in neural repair in the adult central nervous system (CNS) is the long distances that regenerating axons often need to travel in order to reconnect with their targets. Thus, a sustained capacity for axon regeneration is critical for achieving functional restoration. Although deletion of either Phosphatase and tensin homolog (PTEN), a negative regulator of mammalian target of rapamycin (mTOR), or suppressor of cytokine signaling 3 (SOCS3), a negative regulator of Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, in adult retinal ganglion cells (RGCs) individually promoted significant optic nerve regeneration, such regrowth tapered off around two weeks after the crush injury. Remarkably, we now find that simultaneous deletion of both PTEN and SOCS3 enable robust and sustained axon regeneration. We further show that PTEN and SOCS3 regulate two independent pathways that act synergistically to promote enhanced axon regeneration. Gene expression analyses suggest that double deletion not only result in the induction of many growth-related genes, but also allow RGCs to maintain the expression of a repertoire of genes at the physiological level after injury. Our results reveal concurrent activation of mTOR and STAT3 pathways as a key for sustaining long-distance axon regeneration in adult CNS, a crucial step toward functional recovery. RNAs were extracted from FACS sorted YFP positive mouse retinal cells, and gene-profiled using affymetrix 1.0 ST expression arrays. Three hybridizations were performed for each group (Wild type after crush, PTEN Knockout+crush, SOCS3 Knockout+crush, and PTEN/SOCS3 double knockout+crush) with RNA samples collected from three independent FACS purifications. Data were analyzed using dChIP and SAM.

2011-10-27 | E-GEOD-32309 | biostudies-arrayexpress

Sustained axon regeneration induced by a synergy of PTEN and SOCS3 deletion

2011-10-28 | GSE32309 | GEO

Functional Optic Tract Rewiring via Subtype- and Target-specific Axonal Regeneration and Presynaptic Activity Enhancement

Project description:Functional Optic Tract Rewiring via Subtype- and Target-specific Axonal Regeneration and Presynaptic Activity Enhancement

| PRJNA1113667 | ENA

Augmenting fibronectin levels in injured adult CNS promotes axon regeneration in vivo [bulk RNA-seq]

Project description:In an attempt to repair injured central nervous system (CNS) nerves/tracts, immune cells are recruited into the injury site, but endogenous response in adult mammals is insufficient for promoting regeneration of severed axons. Here, we found that a portion of retinal ganglion cell (RGC) CNS projection neurons that survive after optic nerve crush (ONC) injury are enriched for and upregulate fibronectin (Fn)-interacting integrins Itga5 and ItgaV, and that Fn promotes long-term survival and long-distance axon regeneration of a portion of axotomized adult RGCs in culture. We then show that, Fn is developmentally downregulated in the axonal tracts of optic nerve and spinal cord, but injury-activated macrophages/microglia upregulate Fn while axon regeneration-promoting zymosan augments their recruitment (and thereby increases Fn levels) in the injured optic nerve. Finally, we found that Fn’s RGD motif, established to interact with Itga5 and ItgaV, promotes long-term survival and long-distance axon regeneration of adult RGCs after ONC in vivo, with some axons reaching the optic chiasm when co-treated with Rpl7a gene therapy. Thus, experimentally augmenting Fn levels in the injured CNS is a promising approach for therapeutic neuroprotection and axon regeneration of at least a portion of neurons.

2024-06-28 | GSE269813 | GEO

Augmenting fibronectin levels in injured adult CNS promotes axon regeneration in vivo [scRNA-seq]

2024-06-28 | GSE269812 | GEO

Functional Optic Tract Rewiring via Subtype- and Target-specific Axonal Regeneration and Presynaptic Activity Enhancement (scRNA-Seq)

Project description:Functional Optic Tract Rewiring via Subtype- and Target-specific Axonal Regeneration and Presynaptic Activity Enhancement (scRNA-Seq)

| PRJNA1113669 | ENA

Single Cell Transcriptome Analysis of Regenerating RGCs Reveals Potent Glaucoma Neural Repair Genes [First_batch_reg_RGCs]

Project description:Axon regeneration holds great promise for neural repair of CNS axonopathies, including glaucoma. Pten deletion in retinal ganglion cell (RGC) promotes potent optic nerve regeneration, but only a small population of Pten-null RGCs are actually regenerating RGCs (regRGCs); most surviving RGCs (surRGCs) remain non-regenerative. Here we developed a strategy to specifically label and purify regRGCs and surRGCs respectively from the same Pten deletion mice after optic nerve crush, in which they differ only in their regeneration capability. Smart-Seq2 single cell transcriptome analysis revealed novel regeneration-associated genes that significantly promote axon regeneration. The most potent of these, Anxa2, acts synergistically with its ligand tPA in Pten deletion-induced axon regeneration. Anxa2, its downstream effector ILK, and Mpp1 dramatically protect RGC somata and axons and preserves visual function in a clinically relevant model of glaucoma, demonstrating the exciting potential of this innovative strategy to identify novel effective neural repair candidates.

2022-08-20 | GSE206622 | GEO

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