Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Front Mol Neurosci
2017 Feb 07;10:17. doi: 10.3389/fnmol.2017.00017.
Show Gene links
Show Anatomy links
Gene Expression Profiling in the Injured Spinal Cord of Trachemys scripta elegans: An Amniote with Self-Repair Capabilities.
Valentin-Kahan A, García-Tejedor GB, Robello C, Trujillo-Cenóz O, Russo RE, Alvarez-Valin F.
???displayArticle.abstract???
Slider turtles are the only known amniotes with self-repair mechanisms of the spinal cord that lead to substantial functional recovery. Their strategic phylogenetic position makes them a relevant model to investigate the peculiar genetic programs that allow anatomical reconnection in some vertebrate groups but are absent in others. Here, we analyze the gene expression profile of the response to spinal cord injury (SCI) in the turtle Trachemys scripta elegans. We found that this response comprises more than 1000 genes affecting diverse functions: reaction to ischemic insult, extracellular matrix re-organization, cell proliferation and death, immune response, and inflammation. Genes related to synapses and cholesterol biosynthesis are down-regulated. The analysis of the evolutionary distribution of these genes shows that almost all are present in most vertebrates. Additionally, we failed to find genes that were exclusive of regenerating taxa. The comparison of expression patterns among species shows that the response to SCI in the turtle is more similar to that of mice and non-regenerative Xenopus than to Xenopus during its regenerative stage. This observation, along with the lack of conserved "regeneration genes" and the current accepted phylogenetic placement of turtles (sister group of crocodilians and birds), indicates that the ability of spinal cord self-repair of turtles does not represent the retention of an ancestral vertebrate character. Instead, our results suggest that turtles developed this capability from a non-regenerative ancestor (i.e., a lineage specific innovation) that was achieved by re-organizing gene expression patterns on an essentially non-regenerative genetic background. Among the genes activated by SCI exclusively in turtles, those related to anoxia tolerance, extracellular matrix remodeling, and axonal regrowth are good candidates to underlie functional recovery.
Figure 1. Schematic depiction of the experimental pipeline used to generate an “enriched” C. picta mapping reference and subsequent differential gene expression analysis. Further details in section under the title “de novo transcriptome assembly” and Figures S1–S6 in supplementary file.
Figure 2. Distribution of nucleotide identities between T. scripta and C. picta orthologous sequences.
Figure 3. Gene Ontology enrichment analysis of down-regulated genes. Test set refers to the group of differentially expressed (DE) genes (in this case only down-regulated ones) and reference to all genes in the genome. Only some representative (and informative) terms were included in the figure.
Figure 4. Gene Ontology enrichment analysis of genes that are up-regulated. Symbols as in Figure 3. Panels (A–D) show relevant groups of GO terms. The group of GO categories is indicated at the top of each panel.
Figure 5. Protein Interaction network of T. scripta DE genes. Nodes represent genes and lines interactions. Node colors are used to identify the cluster to which the genes belong to. The most relevant cellular processes and functions associated to each cluster are specified by the legend next to it.
Figure 6. Amino acid identity levels of DE genes in species representative of vertebrate taxonomic diversity. Identity levels are indicated by the color scale shown in the top leftmost corner of figure. Values indicate the identity between T. scripta and the species indicated at the bottom of heatmap. Groups of genes for which no ortholog could be found in a given species are presented in separated panels. (A) Genes that are present all the vertebrate species used in this study. Panels (B–F) show genes absent in a particular species, or clade, as indicated in the sub-title of the respective panel. Genes for which an ortholog could not be unambiguously identified in a given species are indicated in violet.
Figure 7. Comparison of gene expression responses between turtles and mice (i) and turtles vs. NR-Xenopus (ii). Panel (A) genes having double coincident behavior are colored in blue and green (for up- and down-regulated, respectively), whereas those exhibiting opposite responses are colored in red and yellow, for up- and down-regulated respectively. Further details about definitions on gene expression behavior in the text. Groups of genes of interest are boxed with dashed lines and shown in greater magnification in panel (B).
Anders,
Differential expression analysis for sequence count data.
2010, Pubmed
Anders,
Differential expression analysis for sequence count data.
2010,
Pubmed Avivi,
Neuroglobin, cytoglobin, and myoglobin contribute to hypoxia adaptation of the subterranean mole rat Spalax.
2010,
Pubmed Bagheri-Yarmand,
Vascular endothelial growth factor up-regulation via p21-activated kinase-1 signaling regulates heregulin-beta1-mediated angiogenesis.
2000,
Pubmed Beck,
Quantitative analysis of cellular inflammation after traumatic spinal cord injury: evidence for a multiphasic inflammatory response in the acute to chronic environment.
2010,
Pubmed Becker,
Axonal regrowth after spinal cord transection in adult zebrafish.
1997,
Pubmed Birukova,
Paxillin is involved in the differential regulation of endothelial barrier by HGF and VEGF.
2009,
Pubmed Bowers,
Methylprednisolone for acute spinal cord injury: an increasingly philosophical debate.
2016,
Pubmed Cabelguen,
Axial dynamics during locomotion in vertebrates lesson from the salamander.
2010,
Pubmed Chadwick,
Multiple oxygen tension environments reveal diverse patterns of transcriptional regulation in primary astrocytes.
2011,
Pubmed Chen,
Testosterone modulation of angiogenesis and neurogenesis in the adult songbird brain.
2013,
Pubmed Chen,
Antiviral immunity in amphibians.
2011,
Pubmed
,
Xenbase Chen,
RNA-seq characterization of spinal cord injury transcriptome in acute/subacute phases: a resource for understanding the pathology at the systems level.
2013,
Pubmed Chevallier,
Recovery of bimodal locomotion in the spinal-transected salamander, Pleurodeles waltlii.
2004,
Pubmed Conesa,
Blast2GO: a universal tool for annotation, visualization and analysis in functional genomics research.
2005,
Pubmed Demircan,
ADAMTS1, ADAMTS5, ADAMTS9 and aggrecanase-generated proteoglycan fragments are induced following spinal cord injury in mouse.
2013,
Pubmed Dias,
Notch signaling controls generation of motor neurons in the lesioned spinal cord of adult zebrafish.
2012,
Pubmed Diaz Quiroz,
Spinal cord regeneration: where fish, frogs and salamanders lead the way, can we follow?
2013,
Pubmed Facchiano,
Promotion of regeneration of corticospinal tract axons in rats with recombinant vascular endothelial growth factor alone and combined with adenovirus coding for this factor.
2002,
Pubmed Fawcett,
The glial scar and central nervous system repair.
1999,
Pubmed Franz,
Gene therapy approaches to enhancing plasticity and regeneration after spinal cord injury.
2012,
Pubmed Gadani,
Dealing with Danger in the CNS: The Response of the Immune System to Injury.
2015,
Pubmed Gaete,
Spinal cord regeneration in Xenopus tadpoles proceeds through activation of Sox2-positive cells.
2012,
Pubmed
,
Xenbase García,
Modulation of gene expression during early stages of reconnection of the turtle spinal cord.
2012,
Pubmed Geng,
Identification of the orphan gene Prod 1 in basal and other salamander families.
2015,
Pubmed Godwin,
Scar-free wound healing and regeneration in amphibians: immunological influences on regenerative success.
2014,
Pubmed
,
Xenbase Goussev,
Differential temporal expression of matrix metalloproteinases after spinal cord injury: relationship to revascularization and wound healing.
2003,
Pubmed Harty,
Regeneration or scarring: an immunologic perspective.
2003,
Pubmed Hashimoto,
Regulation of semaphorin 3A expression in neurons of the rat spinal cord and cerebral cortex after transection injury.
2004,
Pubmed Hedges,
Amniote phylogeny and the position of turtles.
2012,
Pubmed Hedges,
A molecular phylogeny of reptiles.
1999,
Pubmed Herrera,
Reduced vascular endothelial growth factor expression in contusive spinal cord injury.
2009,
Pubmed Horn,
Another barrier to regeneration in the CNS: activated macrophages induce extensive retraction of dystrophic axons through direct physical interactions.
2008,
Pubmed Hui,
Genome wide expression profiling during spinal cord regeneration identifies comprehensive cellular responses in zebrafish.
2014,
Pubmed Iwabe,
Sister group relationship of turtles to the bird-crocodilian clade revealed by nuclear DNA-coded proteins.
2005,
Pubmed Jackson,
Hibernating without oxygen: physiological adaptations of the painted turtle.
2002,
Pubmed Jäderstad,
Communication via gap junctions underlies early functional and beneficial interactions between grafted neural stem cells and the host.
2010,
Pubmed Kaneko,
A selective Sema3A inhibitor enhances regenerative responses and functional recovery of the injured spinal cord.
2006,
Pubmed Kanno,
Regenerative therapy for neuronal diseases with transplantation of somatic stem cells.
2013,
Pubmed Kaufman,
A "minimal essential Mhc" and an "unrecognized Mhc": two extremes in selection for polymorphism.
1995,
Pubmed Kim,
The MMP-9/TIMP-1 axis controls the status of differentiation and function of myelin-forming Schwann cells in nerve regeneration.
2012,
Pubmed Koniski,
Reproducible proliferative responses of salamander (Ambystoma mexicanum) lymphocytes cultured with mitogens in serum-free medium.
1992,
Pubmed Krivoruchko,
Turtle anoxia tolerance: Biochemistry and gene regulation.
2015,
Pubmed Krivoruchko,
Activation of the carbohydrate response element binding protein (ChREBP) in response to anoxia in the turtle Trachemys scripta elegans.
2014,
Pubmed Langmead,
Fast gapped-read alignment with Bowtie 2.
2012,
Pubmed LeComte,
Notch1-STAT3-ETBR signaling axis controls reactive astrocyte proliferation after brain injury.
2015,
Pubmed Lee,
Tumorigenicity as a clinical hurdle for pluripotent stem cell therapies.
2013,
Pubmed Lee-Liu,
Genome-wide expression profile of the response to spinal cord injury in Xenopus laevis reveals extensive differences between regenerative and non-regenerative stages.
2014,
Pubmed
,
Xenbase Li,
Cell transplantation for spinal cord injury: a systematic review.
2013,
Pubmed Lord,
Investigating semantic similarity measures across the Gene Ontology: the relationship between sequence and annotation.
2003,
Pubmed Love,
Amputation-induced reactive oxygen species are required for successful Xenopus tadpole tail regeneration.
2013,
Pubmed
,
Xenbase Love,
Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2.
2014,
Pubmed Lutz,
Is turtle longevity linked to enhanced mechanisms for surviving brain anoxia and reoxygenation?
2003,
Pubmed McKeon,
Reduction of neurite outgrowth in a model of glial scarring following CNS injury is correlated with the expression of inhibitory molecules on reactive astrocytes.
1991,
Pubmed Mecollari,
A perspective on the role of class III semaphorin signaling in central nervous system trauma.
2014,
Pubmed Milton,
Gene transcription of neuroglobin is upregulated by hypoxia and anoxia in the brain of the anoxia-tolerant turtle Trachemys scripta.
2006,
Pubmed Mokalled,
Injury-induced ctgfa directs glial bridging and spinal cord regeneration in zebrafish.
2016,
Pubmed Morrison,
Transient Notch activation initiates an irreversible switch from neurogenesis to gliogenesis by neural crest stem cells.
2000,
Pubmed Nayak,
Role of neuroglobin in regulating reactive oxygen species in the brain of the anoxia-tolerant turtle Trachemys scripta.
2009,
Pubmed Neirinckx,
Concise review: Spinal cord injuries: how could adult mesenchymal and neural crest stem cells take up the challenge?
2014,
Pubmed Nilsson,
Anoxia tolerant brains.
2004,
Pubmed Noble,
Matrix metalloproteinases limit functional recovery after spinal cord injury by modulation of early vascular events.
2002,
Pubmed Pamenter,
delta-Opioid receptor antagonism induces NMDA receptor-dependent excitotoxicity in anoxic turtle cortex.
2008,
Pubmed Park,
The role of excitotoxicity in secondary mechanisms of spinal cord injury: a review with an emphasis on the implications for white matter degeneration.
2004,
Pubmed Patel,
Effect of VEGF treatment on the blood-spinal cord barrier permeability in experimental spinal cord injury: dynamic contrast-enhanced magnetic resonance imaging.
2009,
Pubmed Pék,
Role for adenosine in channel arrest in the anoxic turtle brain.
1997,
Pubmed Rehermann,
Neural reconnection in the transected spinal cord of the freshwater turtle Trachemys dorbignyi.
2009,
Pubmed Rehermann,
Cell proliferation and cytoarchitectural remodeling during spinal cord reconnection in the fresh-water turtle Trachemys dorbignyi.
2011,
Pubmed Reynolds,
Vaccinia virus complement control protein reduces inflammation and improves spinal cord integrity following spinal cord injury.
2004,
Pubmed Rivera,
Metzincin proteases and their inhibitors: foes or friends in nervous system physiology?
2010,
Pubmed Rosenstein,
Neurotrophic effects of vascular endothelial growth factor on organotypic cortical explants and primary cortical neurons.
2003,
Pubmed Rosenstein,
VEGF in the nervous system.
2010,
Pubmed Sánchez Alvarado,
Bridging the regeneration gap: genetic insights from diverse animal models.
2006,
Pubmed Sandner,
Neural stem cells for spinal cord repair.
2012,
Pubmed Shaffer,
The western painted turtle genome, a model for the evolution of extreme physiological adaptations in a slowly evolving lineage.
2013,
Pubmed Shechter,
The glial scar-monocyte interplay: a pivotal resolution phase in spinal cord repair.
2011,
Pubmed Shubayev,
Endoneurial remodeling by TNFalph- and TNFalpha-releasing proteases. A spatial and temporal co-localization study in painful neuropathy.
2002,
Pubmed Shubayev,
Matrix metalloproteinase-9 promotes nerve growth factor-induced neurite elongation but not new sprout formation in vitro.
2004,
Pubmed Silva,
From basics to clinical: a comprehensive review on spinal cord injury.
2014,
Pubmed Storey,
Anoxia tolerance in turtles: metabolic regulation and gene expression.
2007,
Pubmed Sundberg,
Effect of vascular endothelial growth factor treatment in experimental traumatic spinal cord injury: in vivo longitudinal assessment.
2011,
Pubmed Tanaka,
Considering the evolution of regeneration in the central nervous system.
2009,
Pubmed Thomas,
PANTHER: a library of protein families and subfamilies indexed by function.
2003,
Pubmed Torres-Espín,
Gene expression changes in the injured spinal cord following transplantation of mesenchymal stem cells or olfactory ensheathing cells.
2013,
Pubmed Trapnell,
Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks.
2012,
Pubmed Trapnell,
TopHat: discovering splice junctions with RNA-Seq.
2009,
Pubmed Van Elzen,
Expression profiling of the cerebral ischemic and hypoxic response.
2008,
Pubmed van Horssen,
Matrix metalloproteinase-19 is highly expressed in active multiple sclerosis lesions.
2006,
Pubmed Veeravalli,
Human umbilical cord blood stem cells upregulate matrix metalloproteinase-2 in rats after spinal cord injury.
2009,
Pubmed Velardo,
Patterns of gene expression reveal a temporally orchestrated wound healing response in the injured spinal cord.
2004,
Pubmed Verslegers,
Matrix metalloproteinase-2 and -9 as promising benefactors in development, plasticity and repair of the nervous system.
2013,
Pubmed Wells,
An adverse role for matrix metalloproteinase 12 after spinal cord injury in mice.
2003,
Pubmed Widenfalk,
Vascular endothelial growth factor improves functional outcome and decreases secondary degeneration in experimental spinal cord contusion injury.
2003,
Pubmed Zardoya,
The evolutionary position of turtles revised.
2001,
Pubmed Zhang,
Role of matrix metalloproteinases and therapeutic benefits of their inhibition in spinal cord injury.
2011,
Pubmed Zukor,
Meningeal cells and glia establish a permissive environment for axon regeneration after spinal cord injury in newts.
2011,
Pubmed
