XB-ART-57252BMC Genomics August 5, 2020; 21 (1): 540.
Comparative gene expression profiling between optic nerve and spinal cord injury in Xenopus laevis reveals a core set of genes inherent in successful regeneration of vertebrate central nervous system axons.
BACKGROUND: The South African claw-toed frog, Xenopus laevis, is uniquely suited for studying differences between regenerative and non-regenerative responses to CNS injury within the same organism, because some CNS neurons (e.g., retinal ganglion cells after optic nerve crush (ONC)) regenerate axons throughout life, whereas others (e.g., hindbrain neurons after spinal cord injury (SCI)) lose this capacity as tadpoles metamorphose into frogs. Tissues from these CNS regions (frog ONC eye, tadpole SCI hindbrain, frog SCI hindbrain) were used in a three-way RNA-seq study of axotomized CNS axons to identify potential core gene expression programs for successful CNS axon regeneration. RESULTS: Despite tissue-specific changes in expression dominating the injury responses of each tissue, injury-induced changes in gene expression were nonetheless shared between the two axon-regenerative CNS regions that were not shared with the non-regenerative region. These included similar temporal patterns of gene expression and over 300 injury-responsive genes. Many of these genes and their associated cellular functions had previously been associated with injury responses of multiple tissues, both neural and non-neural, from different species, thereby demonstrating deep phylogenetically conserved commonalities between successful CNS axon regeneration and tissue regeneration in general. Further analyses implicated the KEGG adipocytokine signaling pathway, which links leptin with metabolic and gene regulatory pathways, and a novel gene regulatory network with genes regulating chromatin accessibility at its core, as important hubs in the larger network of injury response genes involved in successful CNS axon regeneration. CONCLUSIONS: This study identifies deep, phylogenetically conserved commonalities between CNS axon regeneration and other examples of successful tissue regeneration and provides new targets for studying the molecular underpinnings of successful CNS axon regeneration, as well as a guide for distinguishing pro-regenerative injury-induced changes in gene expression from detrimental ones in mammals.
PubMed ID: 32758133
PMC ID: PMC7430912
Article link: BMC Genomics
Species referenced: Xenopus laevis
Genes referenced: abcb1 acsbg2 aldoa apoe cntrl coq8a cyb5r2 ebf3 enpp2 ezh2 fabp3 fabp7 fads1 fxyd1 hbe1 hes5.1 idh1 irf8 jarid2 kcnn3 kdm7a krt78.5 lep mapk8 mcm6.2 mex3a ocm1 otop3 pdf pkd2 plp1 prmt1 prph rplp1 slc38a4 slc9a3r2 snrpd3 socs3 sox11 suz12 tf ttl tuba1a tubb2b ugt8 znf395
GO keywords: neural tissue regeneration
GEO Series: GSE137844: Xenbase, NCBI
Article Images: [+] show captions
|Fig. 3 Eigenvector representation of the Principal Component Analyses (PCA) of gene expression profiles. Eigenvectors depict relative degrees of similarity among data sets, as indicated. Black points represent individual genes plotted against the principal axes of similarity (PC1, PC2). a, PCA of all 17 experimental conditions and controls. b, PCA of SCI hindbrain samples and their unoperated controls. c, PCA of ONC operated eye expression profiles, as well as those of their paired, contralateral unoperated control eyes and eyes of uninjured animals (surgically naive). Abbreviations: Cntrl, control hindbrain; Juv, juvenile (1–3 month post-metamorphic) frog; ONC, optic nerve crush; PC1, principal component axis 1; PC2, Principal Component axis 2; SCI, spinal cord injured; Tx, spinal cord transection; Unop, unoperated eye, contralateral to the ONC; Wk, week. Additional_File5_PCA_Scatterplot.pdf shows PCA scatterplots|
|Fig. 7. Cellular localization of select DESR genes by in situ hybridization of retina at the peak phase of regenerative axon outgrowth after optic nerve injury. Genes are as indicated in their respective panels and represent a range of fold-change values (0.03 < |log2(fold change)| < 3), and FDRs (0.002–0.05), as well as relatively low (FPKM < 50) and high (FPKM > 100) levels of expression. Examples of up-regulated (a – e) and down-regulated (f, g) genes are included. Column 1 (left), operated eye; column 2 (right), contralateral unoperated eye from the same animal and processed on the same slide as that of its adjacent column. Arrows indicate cells of the retinal ganglion cell layer, which comprises the neurons that regenerate an axon. Abbreviations: RGC, retinal ganglion cells; INL, inner nuclear layer; PR, photoreceptors. Scale bar in G2 applies to all panels|
|Additional File 5 Scatterplot representation of the Principal Component Analyses (PCA) of gene expression profiles. Ellipses group biological replicates for each indicated condition (experimentals, solid squares; controls, empty squares), indicating variation among samples. AC, PCA of tadpole and juvenile hindbrain after spinal cord injury (SCI), and of juvenile frog after optic nerve crush (ONC), respectively. In C, expression profiles from the operated eye were compared with those of the contralateral, unoperated eyes within the same animals. D, PCA of all 17 conditions combined, supporting the tissue-specific nature of gene expression profiles. Conditions were the same as in AC, except that data from eyes of animals receiving no injury was included (open triangles, Frog Eye, Unop). E, PCA of tadpole and juvenile frog hindbrain samples after spinal cord injury, supporting the conclusion that the differences in gene expression profiles between the time points at which numbers of differentially expressed genes reached their peaks (3 days in juvenile frog hindbrain and 1 week in tadpole hindbrain) were more than just a kinetic difference in the timing of expression of the same differentially expressed genes. Abbreviations: ONC, optic nerve crush; PC1, principal component axis 1; PC2, Principal Component axis 2; SCI, spinal cord injured; TX, spinal cord transected; Unop ONC unoperated eye, contralateral to the operated eye; Frog Eye, Unop eyes from unoperated animals; wk, week.|
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Abe, Mammalian target of rapamycin (mTOR) activation increases axonal growth capacity of injured peripheral nerves. 2010, Pubmed