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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 | GSE267935 | GEO
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
Project description:Functional Optic Tract Rewiring via Subtype- and Target-specific Axonal Regeneration and Presynaptic Activity Enhancement
| PRJNA1113667 | ENA
Project description:Functional Optic Tract Rewiring via Subtype- and Target-specific Axonal Regeneration and Presynaptic Activity Enhancement (scRNA-Seq)
| PRJNA1113669 | ENA
Project description:Functional Optic Tract Rewiring via Subtype- and Target-specific Axonal Regeneration and Presynaptic Activity Enhancement (bulk RNA-Seq)
| PRJNA1113670 | ENA
Project description:Semaphorin 3A (Sema3A) is a cell-secreted protein that participates in the axonal guidance pathways. Sema3A acts as a canonical repulsive axon guidance molecule, inhibiting CNS regenerative axonal growth and propagation. Therefore, interfering with Sema3A signaling is proposed as a therapeutic target for achieving functional recovery after CNS injuries. It has been shown that Sema3A adheres to the proteoglycan component of the extracellular matrix (ECM) and selectively binds to heparin and chondroitin sulfate-E (CS-E) glycosaminoglycans (GAGs). We hypothesize that the biologically relevant interaction between Sema3A and GAGs takes place at Sema3A C-terminal polybasic region (SCT). The aims of this study were to characterize the interaction of the whole Sema3A C-terminal polybasic region (Sema3A 725-771) with GAGs and to investigate the disruption of this interaction by small molecules. Recombinant Sema3A basic domain was produced and we used a combination of biophysical techniques (NMR, SPR, and heparin affinity chromatography) to gain insight into the interaction of the Sema3A C-terminal domain with GAGs. The results demonstrate that SCT is an intrinsically disordered region, which confirms that SCT binds to GAGs and helps to identify the specific residues involved in the interaction. NMR studies, supported by molecular dynamics simulations, show that a new peptoid molecule (CSIC02) may disrupt the interaction between SCT and heparin. Our structural study paves the way toward the design of new molecules targeting these protein-GAG interactions with potential therapeutic applications.
| S-EPMC8465649 | biostudies-literature
Project description:Regeneration following spinal root avulsion is broadly unsuccessful despite the regenerative capacity of other PNS-located nerves. By combining focal laser lesioning to model root avulsion in zebrafish, time-lapse imaging, and transgenesis, we identify that regenerating DRG neurons fail to recapitulate developmental paradigms of actin-based invasion after injury. We demonstrate that inducing actin reorganization into invasive components via pharmacological and genetic approaches in the regenerating axon can rescue sensory axon spinal cord entry. Cell-autonomous induction of invasion components using constitutively active Src induces DRG axon regeneration, suggesting an intrinsic mechanism can be activated to drive regeneration. Furthermore, analyses of neuronal activity and animal behavior show restoration of sensory circuit activity and behavior upon stimulating axons to re-enter the spinal cord via invasion. Altogether, our data identify induction of invasive components as sufficient for functional sensory root regeneration after injury.
| S-EPMC6996490 | biostudies-literature
Project description:Axonal degeneration occurs in various neurological diseases and traumatic nerve injury, and axonal regeneration is restricted by inhibitory factors in the central nervous system. Cyclin-dependent kinase 5 and glycogen synthase kinase 3β (GSK3β) are activated by one of those inhibitors, and collapsin response mediator protein 2 (CRMP2) is phosphorylated by both kinases. We previously developed a CRMP2 knock-in (CRMP2 KI) mouse line, in which CRMP2 phosphorylation at Ser 522 is inhibited. Because CRMP2 KI mice showed promotion of axonal regeneration after spinal cord injury, we hypothesized that CRMP2 KI mice would show higher axonal regeneration after optic nerve injury. In this study, we first show that depolymerization of microtubules after optic nerve crush (ONC) injury was suppressed in CRMP2 KI mice. Loss of retinal ganglia cells was also reduced after ONC. We found that protein level of GAP43, a marker of regenerative axons, was higher in the optic nerve from CRMP2KI than that from wild type 4 weeks after of ONC. We further observed increased numbers of axons labeled by tracer in the optic nerve after ONC in CRMP2 KI mice. These results suggest that inhibition of phosphorylation of CRMP2 suppresses axonal degeneration and promotes axonal regeneration after optic nerve injury.
| S-EPMC6510754 | biostudies-literature
Project description:The neurodegenerative disease glaucoma is characterised by the progressive death of retinal ganglion cells (RGCs) and structural damage to the optic nerve (ON). New insights have been gained into the pathogenesis of glaucoma through the use of rodent models; however, a coherent picture of the early pathology remains elusive. Here, we use a validated, experimentally induced rat glaucoma model to address fundamental issues relating to the spatio-temporal pattern of RGC injury. The earliest indication of RGC damage was accumulation of proteins, transported by orthograde fast axonal transport within axons in the optic nerve head (ONH), which occurred as soon as 8 h after induction of glaucoma and was maximal by 24 h. Axonal cytoskeletal abnormalities were first observed in the ONH at 24 h. In contrast to the ONH, no axonal cytoskeletal damage was detected in the entire myelinated ON and tract until 3 days, with progressively greater damage at later time points. Likewise, down-regulation of RGC-specific mRNAs, which are sensitive indicators of RGC viability, occurred subsequent to axonal changes at the ONH and later than in retinas subjected to NMDA-induced somatic excitotoxicity. After 1 week, surviving, but injured, RGCs had initiated a regenerative-like response, as delineated by Gap43 immunolabelling, in a response similar to that seen after ON crush. The data presented here provide robust support for the hypothesis that the ONH is the pivotal site of RGC injury following moderate elevation of IOP, with the resulting anterograde degeneration of axons and retrograde injury and death of somas.
| S-EPMC3098991 | biostudies-literature
Project description:Neuritin 1 (Nrn1) is an extracellular glycophosphatidylinositol-linked protein that stimulates axonal plasticity, dendritic arborization and synapse maturation in the central nervous system (CNS). The purpose of this study was to evaluate the neuroprotective and axogenic properties of Nrn1 on axotomized retinal ganglion cells (RGCs) in vitro and on the in vivo optic nerve crush (ONC) mouse model. Axotomized cultured RGCs treated with recombinant hNRN1 significantly increased survival of RGCs by 21% (n=6-7, P<0.01) and neurite outgrowth in RGCs by 141% compared to controls (n=15, P<0.05). RGC transduction with AAV2-CAG-hNRN1 prior to ONC promoted RGC survival (450%, n=3-7, P<0.05) and significantly preserved RGC function by 70% until 28 days post crush (dpc) (n=6, P<0.05) compared with the control AAV2-CAG-green fluorescent protein transduction group. Significantly elevated levels of RGC marker, RNA binding protein with multiple splicing (Rbpms; 73%, n=5-8, P<0.001) and growth cone marker, growth-associated protein 43 (Gap43; 36%, n=3, P<0.01) were observed 28 dpc in the retinas of the treatment group compared with the control group. Significant increase in Gap43 (100%, n=5-6, P<0.05) expression was observed within the optic nerves of the AAV2-hNRN1 group compared to controls. In conclusion, Nrn1 exhibited neuroprotective, regenerative effects and preserved RGC function on axotomized RGCs in vitro and after axonal injury in vivo. Nrn1 is a potential therapeutic target for CNS neurodegenerative diseases.
| S-EPMC4669798 | biostudies-other