Faculty Opinions recommendation of The growth factor SVH-1 regulates axon regeneration in C. elegans via the JNK MAPK cascade.

AbstractStudies have found that molecular targets that regulate tissue development are also involved in regulating tissue regeneration. Erythropoietin-producing hepatocyte A4 (EphA4) not only plays a guiding role in neurite outgrowth during the development of the central nervous system (CNS) but also induces injured axon retraction and inhibits axon regeneration after spinal cord injury (SCI). EphA4 targets several ephrin ligands (including ephrin-A and ephrin-B) and is involved in cortical cell migration, axon guidance, synapse formation and astrocyte function. However, how EphA4 affects axon regeneration after SCI remains unclear. This study focuses on the effect and mechanism of EphA4-regulated astrocyte function in neuronal regeneration after SCI. Our research found that EphA4 expression increased significantly after SCI and peaked at 3 days post-injury; accordingly, we identified the cellular localization of EphA4 and ephrin-B ligands in neurons and astrocytes after SCI. EphA4 was mainly expressed on the surface of neurons, ephrin-B1 and ephrin-B3 were mainly localized on astrocytes, and ephrin-B2 was distributed on both neurons and astrocytes. To further elucidate the effect of EphA4 on astrocyte function after SCI, we detected the related cytokines secreted by astrocytes in vivo. We found that the levels of neurotrophic factors including nerve growth factor (NGF) and basic fibroblast growth factor (bFGF) increased significantly after SCI (NGF peaked at 3 days and bFGF peaked at 7 days); the expression of laminin and fibronectin increased gradually after SCI; the expression of inflammatory factors [interleukin (IL)-1β and IL-6] increased significantly from 4 h to 7 days after SCI; and the levels of glial fibrillary acidic protein (GFAP), a marker of astrocyte activation, and chondroitin sulphate proteoglycan (CSPG), the main component of glial scars, both peaked at 7 days after SCI. Using a damaged astrocyte model in vitro, we similarly found that the levels of related cytokines increased after injury. Consequently, we observed the effect of damaged astrocytes on neurite outgrowth and regeneration, and the results showed that damaged astrocytes hindered neurite outgrowth and regeneration; however, the inhibitory effect of injured astrocytes on neurite regeneration was reduced following ephrin-B receptor knockdown or inflammatory inhibition at 24 h after astrocyte injury. Our results showed that EphA4 regulates the secretion of neurotrophic factors, adhesion molecules, inflammatory factors and glial scar formation by binding with the ligand ephrin-B located on the surface of astrocytes. EphA4 affects neurite outgrowth and regeneration after SCI by regulating astrocyte function.

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Extracellular signal-regulated kinases 1/2 are required for adult retinal ganglion cell axon regeneration induced by fibroblast growth factor-2

Journal of Neuroscience Research ◽

10.1002/jnr.20803 ◽

2006 ◽

Vol 83 (6) ◽

pp. 985-995 ◽

Cited By ~ 17

Author(s):

Przemyslaw S. Sapieha ◽

William W. Hauswirth ◽

Adriana Di Polo

Keyword(s):

Growth Factor ◽

Ganglion Cell ◽

Fibroblast Growth Factor ◽

Retinal Ganglion Cell ◽

Axon Regeneration ◽

Fibroblast Growth Factor 2 ◽

Retinal Ganglion ◽

Fibroblast Growth ◽

Extracellular Signal ◽

Ganglion Cell Axon

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rab-27 acts in an intestinal pathway to inhibit axon regeneration in C. elegans

PLoS Genetics ◽

10.1371/journal.pgen.1009877 ◽

2021 ◽

Vol 17 (11) ◽

pp. e1009877

Author(s):

Alexander T. Lin-Moore ◽

Motunrayo J. Oyeyemi ◽

Marc Hammarlund

Keyword(s):

Motor Neurons ◽

Axon Regeneration ◽

Rab Gtpase ◽

Long Distance ◽

Extrinsic Factors ◽

C Elegans ◽

Cellular Environment ◽

Neuropeptide Secretion ◽

Neuronal Tissues ◽

Nervous System Function

Injured axons must regenerate to restore nervous system function, and regeneration is regulated in part by external factors from non-neuronal tissues. Many of these extrinsic factors act in the immediate cellular environment of the axon to promote or restrict regeneration, but the existence of long-distance signals regulating axon regeneration has not been clear. Here we show that the Rab GTPase rab-27 inhibits regeneration of GABAergic motor neurons in C. elegans through activity in the intestine. Re-expression of RAB-27, but not the closely related RAB-3, in the intestine of rab-27 mutant animals is sufficient to rescue normal regeneration. Several additional components of an intestinal neuropeptide secretion pathway also inhibit axon regeneration, including NPDC1/cab-1, SNAP25/aex-4, KPC3/aex-5, and the neuropeptide NLP-40, and re-expression of these genes in the intestine of mutant animals is sufficient to restore normal regeneration success. Additionally, NPDC1/cab-1 and SNAP25/aex-4 genetically interact with rab-27 in the context of axon regeneration inhibition. Together these data indicate that RAB-27-dependent neuropeptide secretion from the intestine inhibits axon regeneration, and point to distal tissues as potent extrinsic regulators of regeneration.

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CELF RNA binding proteins promote axon regeneration in C. elegans and mammals through alternative splicing of Syntaxins

eLife ◽

10.7554/elife.16072 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 13

Author(s):

Lizhen Chen ◽

Zhijie Liu ◽

Bing Zhou ◽

Chaoliang Wei ◽

Yu Zhou ◽

...

Keyword(s):

Gene Expression ◽

Transcriptional Regulation ◽

Alternative Splicing ◽

Binding Proteins ◽

Rna Binding ◽

Axon Regeneration ◽

Rna Binding Proteins ◽

Mrna Isoforms ◽

C Elegans ◽

Mrna Targets

Axon injury triggers dramatic changes in gene expression. While transcriptional regulation of injury-induced gene expression is widely studied, less is known about the roles of RNA binding proteins (RBPs) in post-transcriptional regulation during axon regeneration. In C. elegans the CELF (CUGBP and Etr-3 Like Factor) family RBP UNC-75 is required for axon regeneration. Using crosslinking immunoprecipitation coupled with deep sequencing (CLIP-seq) we identify a set of genes involved in synaptic transmission as mRNA targets of UNC-75. In particular, we show that UNC-75 regulates alternative splicing of two mRNA isoforms of the SNARE Syntaxin/unc-64. In C. elegans mutants lacking unc-75 or its targets, regenerating axons form growth cones, yet are deficient in extension. Extending these findings to mammalian axon regeneration, we show that mouse Celf2 expression is upregulated after peripheral nerve injury and that Celf2 mutant mice are defective in axon regeneration. Further, mRNAs for several Syntaxins show CELF2 dependent regulation. Our data delineate a post-transcriptional regulatory pathway with a conserved role in regenerative axon extension.

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Effects of NAD+ in Caenorhabditis elegans Models of Neuronal Damage

Biomolecules ◽

10.3390/biom10070993 ◽

2020 ◽

Vol 10 (7) ◽

pp. 993

Author(s):

Yuri Lee ◽

Hyeseon Jeong ◽

Kyung Hwan Park ◽

Kyung Won Kim

Keyword(s):

Caenorhabditis Elegans ◽

Therapeutic Strategy ◽

Axon Regeneration ◽

Neuronal Damage ◽

Biological Processes ◽

Nematode Caenorhabditis Elegans ◽

C Elegans ◽

Neuronal Functions ◽

Molecular Components

Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor that mediates numerous biological processes in all living cells. Multiple NAD+ biosynthetic enzymes and NAD+-consuming enzymes are involved in neuroprotection and axon regeneration. The nematode Caenorhabditis elegans has served as a model to study the neuronal role of NAD+ because many molecular components regulating NAD+ are highly conserved. This review focuses on recent findings using C. elegans models of neuronal damage pertaining to the neuronal functions of NAD+ and its precursors, including a neuroprotective role against excitotoxicity and axon degeneration as well as an inhibitory role in axon regeneration. The regulation of NAD+ levels could be a promising therapeutic strategy to counter many neurodegenerative diseases, as well as neurotoxin-induced and traumatic neuronal damage.

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The Chromatin Remodeler LET-418/Mi2 is Required Cell Non-Autonomously for the Post-Embryonic Development of Caenorhabditis elegans

Journal of Developmental Biology ◽

10.3390/jdb7010001 ◽

2018 ◽

Vol 7 (1) ◽

pp. 1 ◽

Cited By ~ 2

Author(s):

Makhabbat Saudenova ◽

Chantal Wicky

Keyword(s):

Growth Factor ◽

Embryonic Development ◽

Progenitor Cells ◽

Growth Factor Signaling ◽

Chromatin Protein ◽

C Elegans ◽

Blast Cells ◽

A Cell ◽

Further Development ◽

Growth Factor Signaling Pathway

Chromatin condition is crucial for the cells to respond to their environment. In C. elegans, post-embryonic development is accompanied by the exit of progenitor cells from quiescence in response to food. The chromatin protein LET-418/Mi2 is required for this transition in development indicating that proper chromatin structure in cells of the freshly hatched larvae is important to respond to food. However, the identity of the tissue or cells where LET-418/Mi2 is required, as well as the developmental signals that it is modulating have not been elucidated. By restoring the activity of LET-418/Mi2 in specific tissues, we demonstrate that its activity in the intestine and the hypodermis is able to promote in a cell non-autonomous manner the exit of blast cells from quiescence and further development. Furthermore, we identify the IIS (insulin/insulin-like growth factor signaling) pathway to be one of the signaling pathways that is conveying LET-418/Mi2 cell non-autonomous effect on development.

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