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Developmentally upregulated transcriptional elongation factor a like 3 suppresses axon regeneration after optic nerve injury.

ABSTRACT: Projection neurons of the mammalian central nervous system (CNS) do not spontaneously regenerate axons which have been damaged by an injury or disease, often leaving patients with permanent disabilities that affect motor, cognitive, or sensory functions. Although several molecular targets which promote some extent of axon regeneration in animal models have been identified, the resulting recovery is very limited, and the molecular mechanisms underlying the axonal regenerative failure in the CNS are still poorly understood. One of the most studied targets for axon regeneration in the CNS is the mTOR pathway. A number of developmentally regulated genes also have been found to play a role in CNS axon regeneration. Here, we found that Transcriptional Elongation Factor A Like 3 (Tceal3), belonging to the Bex/Tceal transcriptional regulator family, which also modulates the mTOR pathway, is developmentally upregulated in retinal ganglion cell (RGCs) projection CNS neurons, and suppresses their capacity to regenerate axons after injury.

SUBMITTER: Lukomska A

PROVIDER: S-EPMC8572158 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Topical ripasudil stimulates neuroprotection and axon regeneration in adult mice following optic nerve injury.

Project description:Optic nerve injury induces optic nerve degeneration and retinal ganglion cell (RGC) death that lead to visual disturbance. In this study, we examined if topical ripasudil has therapeutic potential in adult mice after optic nerve crush (ONC). Topical ripasudil suppressed ONC-induced phosphorylation of p38 mitogen-activated protein kinase and ameliorated RGC death. In addition, topical ripasudil significantly suppressed the phosphorylation of collapsin response mediator protein 2 and cofilin, and promoted optic nerve regeneration. These results suggest that topical ripasudil promotes RGC protection and optic nerve regeneration by modulating multiple signaling pathways associated with neural cell death, microtubule assembly and actin polymerization.

| S-EPMC7515881 | biostudies-literature

Upregulating Lin28a Promotes Axon Regeneration in Adult Mice with Optic Nerve and Spinal Cord Injury.

Project description:Severed CNS axons fail to regenerate in adult mammals and there are no effective regenerative strategies to treat patients with CNS injuries. Several genes, including phosphatase and tensin homolog (PTEN) and Krüppel-like factors, regulate intrinsic growth capacity of mature neurons. The Lin28 gene is essential for cell development and pluripotency in worms and mammals. In this study, we evaluated the role of Lin28a in regulating regenerative capacity of diverse populations of CNS neurons in adult mammals. Using a neuron-specific Thy1 promoter, we generated transgenic mice that overexpress Lin28a protein in multiple populations of projection neurons, including corticospinal tracts and retinal ganglion cells. We demonstrate that upregulation of Lin28a in transgenic mice induces significant long distance regeneration of both corticospinal axons and the optic nerve in adult mice. Importantly, overexpression of Lin28a by post-injury treatment with adeno-associated virus type 2 (AAV2) vector stimulates dramatic regeneration of descending spinal tracts and optic nerve axons after lesions. Upregulation of Lin28a also enhances activity of the Akt signaling pathway in mature CNS neurons. Therefore, Lin28a is critical for regulating growth capacity of multiple CNS neurons and may become an important molecular target for treating CNS injuries.

| S-EPMC7403348 | biostudies-literature

Retinal ganglion cell survival and axon regeneration after optic nerve injury in naked mole-rats.

Project description:In the adult mammalian central nervous system (CNS), axonal damage often triggers neuronal cell death and glial activation, with very limited spontaneous axon regeneration. In this study, we performed optic nerve injury in adult naked mole-rats, the longest living rodent, with a maximum life span exceeding 30 years, and found that injury responses in this species are quite distinct from those in other mammalian species. In contrast to what is seen in other mammals, the majority of injured retinal ganglion cells (RGCs) survive with relatively high spontaneous axon regeneration. Furthermore, injured RGCs display activated signal transducer and activator of transcription-3 (STAT3), whereas astrocytes in the optic nerve robustly occupy and fill the lesion area days after injury. These neuron-intrinsic and -extrinsic injury responses are reminiscent of those in "cold-blooded" animals, such as fish and amphibians, suggesting that the naked mole-rat is a powerful model for exploring the mechanisms of neuronal injury responses and axon regeneration in mammals. J. Comp. Neurol. 525:380-388, 2017. © 2016 Wiley Periodicals, Inc.

| S-EPMC6422164 | biostudies-literature

Experimental gene expression of developmentally downregulated Crmp1, Crmp4, and Crmp5 promotes axon regeneration and retinal ganglion cell survival after optic nerve injury.

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-04-10 | GSE228487 | GEO

Circ-Spidr enhances axon regeneration after peripheral nerve injury.

Project description:Accumulating evidence suggests that circular RNAs (circRNAs) are abundant and play critical roles in the nervous system. However, their functions in axon regeneration after neuronal injury are unclear. Due to its robust regeneration capacity, peripheral nervous system is ideal for seeking the regulatory circRNAs in axon regeneration. In the present work, we obtained an expression profile of circRNAs in dorsal root ganglions (DRGs) after rat sciatic nerve crush injury by RNA sequencing (RNA-Seq) and found the expression level of circ-Spidr was obviously increased using quantitative real-time polymerase chain reaction (qRT-PCR). Furthermore, circ-Spidr was proved to be a circular RNA enriched in the cytoplasm of DRG neurons. Through in vitro and in vivo experiments, we determined that down-regulation of circ-Spidr could suppress axon regeneration of DRG neurons after sciatic nerve injury partially through modulating PI3K-Akt signaling pathway. Together, our results reveal a crucial role for circRNAs in regulating axon regeneration after neuronal injury which may further serve as a potential therapeutic avenue for neuronal injury repair.

| S-EPMC6797756 | biostudies-literature

Experimental gene expression of developmentally downregulated Crmp1, Crmp4, and Crmp5 promotes axon regeneration and retinal ganglion cell survival after optic nerve injury [bulk RNA-seq]

Project description:Collapsin response mediator proteins (Crmps) play roles in neuronal development and axon growth. However, neuronal-specific roles of Crmp1, Crmp4, and Crmp5 in regeneration of injured central nervous system (CNS) axons in vivo are unclear. Here, we analyzed developmental and subtype-specific expression of Crmp genes in retinal ganglion cells (RGCs), tested whether overexpressing Crmp1, Crmp4, or Crmp5 in RGCs through localized intralocular AAV2 delivery promotes axon regeneration after optic nerve injury in vivo, and characterized developmental co-regulation of gene-concept networks associated with Crmps. We found that all Crmp genes are developmentally downregulated in RGCs during maturation. However, while Crmp1, Crmp2, and Crmp4 were expressed to a varying degree in most RGC subtypes, Crmp3 and Crmp5 were expressed only in a small subset of RGC subtypes. We then found that after optic nerve injury, Crmp1, Crmp4, and Crmp5 promote RGC axon regeneration to varying extents, with Crmp4 promoting the most axon regeneration and also localizing to axons. We also found that Crmp1 and Crmp4, but not Crmp5, promote RGC survival. Finally, we found that Crmp1, Crmp2, Crmp4, and Crmp5's ability to promote axon regeneration is associated with neurodevelopmental mechanisms, which control RGC’s intrinsic axon growth capacity.

2023-04-10 | GSE228485 | GEO

Betacellulin regulates peripheral nerve regeneration by affecting Schwann cell migration and axon elongation.

Project description:BackgroundGrowth factors execute essential biological functions and affect various physiological and pathological processes, including peripheral nerve repair and regeneration. Our previous sequencing data showed that the mRNA coding for betacellulin (Btc), an epidermal growth factor protein family member, was up-regulated in rat sciatic nerve segment after nerve injury, implying the potential involvement of Btc during peripheral nerve regeneration.MethodsExpression of Btc was examined in Schwann cells by immunostaining. The function of Btc in regulating Schwann cells was investigated by transfecting cultured cells with siRNA segment against Btc or treating cells with Btc recombinant protein. The influence of Schwann cell-secreted Btc on neurons was determined using a co-culture assay. The in vivo effects of Btc on Schwann cell migration and axon elongation after rat sciatic nerve injury were further evaluated.ResultsImmunostaining images and ELISA outcomes indicated that Btc was present in and secreted by Schwann cells. Transwell migration and wound healing observations showed that transfection with siRNA against Btc impeded Schwann cell migration while application of exogenous Btc advanced Schwann cell migration. Besides the regulating effect on Schwann cell phenotype, Btc secreted by Schwann cells influenced neuron behavior and increased neurite length. In vivo evidence supported the promoting role of Btc in nerve regeneration after both rat sciatic nerve crush injury and transection injury.ConclusionOur findings demonstrate the essential roles of Btc on Schwann cell migration and axon elongation and imply the potential application of Btc as a regenerative strategy for treating peripheral nerve injury.

| S-EPMC8015203 | biostudies-literature

Experimental gene expression of developmentally downregulated Crmp1, Crmp4, and Crmp5 promotes axon regeneration and retinal ganglion cell survival after optic nerve injury [third-party re-analysis]

2023-04-10 | GSE228486 | GEO

Spermidine promotes retinal ganglion cell survival and optic nerve regeneration in adult mice following optic nerve injury.

Project description:Spermidine acts as an endogenous free radical scavenger and inhibits the action of reactive oxygen species. In this study, we examined the effects of spermidine on retinal ganglion cell (RGC) death in a mouse model of optic nerve injury (ONI). Daily ingestion of spermidine reduced RGC death following ONI and sequential in vivo retinal imaging revealed that spermidine effectively prevented retinal degeneration. Apoptosis signal-regulating kinase-1 (ASK1) is an evolutionarily conserved mitogen-activated protein kinase kinase kinase and has an important role in ONI-induced RGC apoptosis. We demonstrated that spermidine suppresses ONI-induced activation of the ASK1-p38 mitogen-activated protein kinase pathway. Moreover, production of chemokines important for microglia recruitment was decreased with spermidine treatment and, consequently, accumulation of retinal microglia is reduced. In addition, the ONI-induced expression of inducible nitric oxide synthase in the retina was inhibited with spermidine treatment, particularly in microglia. Furthermore, daily spermidine intake enhanced optic nerve regeneration in vivo. Our findings indicate that spermidine stimulates neuroprotection as well as neuroregeneration, and may be useful for treatment of various neurodegenerative diseases including glaucoma.

| S-EPMC4650557 | biostudies-other

Coordinated stimulation of axon regenerative and neurodegenerative transcriptional programs by Atf4 following optic nerve injury

Project description:To understand the contributions of the Integrated Stress Response (ISR) to the axon regenerative and neurodegenerative transcriptional programs activated by axon injury in the CNS, we evaluated by RNA-seq the retinal transcriptomes of conditional knockout mouse lines for components of the ISR three days after optic nerve crush injury. Prior to injury, intravitreal injection of AAV2-mTagBFP2-ires-Cre under the control of the human synapsin-1 promoter facilitated neuron-specific knockout of Eif2ak3, the gene that encodes the ER stress-responsive kinase Perk; Atf4, the gene that encodes the ISR mediator Activating transcription factor-4; or Ddit3, the gene that encodes another transcription factor that can mediate the ISR, C/ebp homologous protein, or CHOP. We compared the expression profiles of these transgenic retinas after injury to retinas from wildtype mice with and without injury to identify transcripts whose regulation by axon injury is dependent on ISR signaling.

2023-03-30 | GSE223321 | GEO

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