title: CELF RNA binding proteins promote axon regeneration in C. elegans and mammals through alternative splicing of Syntaxins.
abstract: 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.
authors.affiliation: Section of Neurobiology, University of California, San Diego, Division of Biological Sciences, San Diego, United States.|Howard Hughes Medical Institute, University of California, San Diego, United States.
authors.forename: Lizhen
authors.identifier: 0000-0001-5313-7340
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Medicine, University of California, San Diego, School of Medicine, San Diego, United States.
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, School of Medicine, San Diego, United States.
authors.forename: Bing
authors.identifier: 0000-0003-2846-1813
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, School of Medicine, San Diego, United States.
authors.forename: Chaoliang
authors.initials: C
authors.lastname: Wei
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, School of Medicine, San Diego, United States.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Howard Hughes Medical Institute, University of California, San Diego, United States.|Department of Medicine, University of California, San Diego, School of Medicine, San Diego, United States.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rosenfeld
authors.affiliation: Department of Cellular and Molecular Medicine, University of California, San Diego, School of Medicine, San Diego, United States.
authors.forename: Xiang-Dong
authors.initials: XD
authors.lastname: Fu
authors.affiliation: Section of Neurobiology, University of California, San Diego, Division of Biological Sciences, San Diego, United States.
authors.forename: Andrew D
authors.identifier: 0000-0001-5091-0537
authors.initials: AD
authors.lastname: Chisholm
authors.affiliation: Section of Neurobiology, University of California, San Diego, Division of Biological Sciences, San Diego, United States.|Howard Hughes Medical Institute, University of California, San Diego, United States.|Department of Cellular and Molecular Medicine, University of California, San Diego, School of Medicine, San Diego, United States.
authors.forename: Yishi
authors.identifier: 0000-0002-9371-9860
authors.initials: Y
authors.lastname: Jin
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D001369:Axons / Q000502:physiology*; D000067878:CELF Proteins / Q000235:genetics / Q000378:metabolism*; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D008124:Locomotion; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D059348:Peripheral Nerve Injuries / Q000378:metabolism / Q000473:pathology; D020033:Protein Isoforms; D050765:Qa-SNARE Proteins / Q000235:genetics* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D012038:Regeneration
chemical_list: D000067878:CELF Proteins; D029742:Caenorhabditis elegans Proteins; C544452:Celf2 protein, mouse; D020033:Protein Isoforms; D050765:Qa-SNARE Proteins; D016601:RNA-Binding Proteins; C581735:UNC-75 protein, C elegans
keywords: C. elegans; CUGBP; DRG; PNS regeneration; UNC-75; mouse; neurite outgrowth; neuroscience; post-transcriptional regulation