CELF RNA binding proteins promote axon regeneration in C. elegans and mouse through regulation of syntaxin
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA312625 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR3179955.fastq.gz | Fastqsanger.gz | |||
| SRR3179956.fastq.gz | Fastqsanger.gz |
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Project description: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. CLIP-seq and expression analysis also reveal CELF2 dependent regulation of selective syntaxins. Our data delineate a post-transcriptional regulatory pathway with a conserved role in regenerative axon extension.
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Project description:Current treatments for neurodegenerative diseases and neural injuries fall short of success. One primary reason is that neurons in the mammalian central nervous system (CNS) lose their regeneration ability as they mature. Here, we investigated the role of Ezh2, a histone methyltransferase, in regulation of mammalian axon regeneration. We found that Ezh2 declined in the mouse nervous system during maturation but was upregulated in adult dorsal root ganglion neurons to support spontaneous axon regeneration following peripheral nerve injury. In addition, overexpression of Ezh2 in retinal ganglion cells in the CNS promoted optic nerve regeneration via both histone methylation-dependent and -independent mechanisms. Further investigation revealed that Ezh2 supported axon regeneration by systematically silencing the transcription of genes regulating synaptic function and inhibiting axon regeneration, while simultaneously activating various axon regeneration promoting factors. In particular, our study demonstrated that the GABA transporter 2 encoded by the gene Slc6a13 acted downstream of Ezh2 to control axon regeneration. Our study suggested that modulating chromatin accessibility was a promising strategy to promote CNS axon regeneration.
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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.
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Project description:Current treatments for neurodegenerative diseases and neural injuries fall short of success. One primary reason is that neurons in the mammalian central nervous system (CNS) lose their regeneration ability as they mature. Here, we investigated the role of Ezh2, a histone methyltransferase, in regulation of mammalian axon regeneration. We found that Ezh2 declined in the mouse nervous system during maturation but was upregulated in adult dorsal root ganglion neurons to support spontaneous axon regeneration following peripheral nerve injury. In addition, overexpression of Ezh2 in retinal ganglion cells in the CNS promoted optic nerve regeneration via both histone methylation-dependent and -independent mechanisms. Further investigation revealed that Ezh2 supported axon regeneration by systematically silencing the transcription of genes regulating synaptic function and inhibiting axon regeneration, while simultaneously activating various axon regeneration promoting factors. In particular, our study demonstrated that the GABA transporter 2 encoded by the gene Slc6a13 acted downstream of Ezh2 to control axon regeneration. Our study suggested that modulating chromatin accessibility was a promising strategy to promote CNS axon regeneration.
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