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• W2290464187 abstract "In this issue, Chandran et al., 2016Chandran V. Coppola G. Nawabi H. Omura T. Versano R. Huebner E.A. Zhang A. Costigan M. Yekkirala A. Barrett L. et al.Neuron. 2016; 89 (this issue): 956-970Abstract Full Text Full Text PDF Scopus (218) Google Scholar pursue a multi-level bioinformatics approach combined with wet bench validation to identify gene networks associated with the regenerative state of injured adult sensory neurons. A small molecular compound, ambroxol, mimics aspects of the identified gene expression patterns and promotes axon regeneration in the injured adult mouse CNS, demonstrating feasibility of in silico-based methods to identify compounds that promote neuronal growth following CNS injury. In this issue, Chandran et al., 2016Chandran V. Coppola G. Nawabi H. Omura T. Versano R. Huebner E.A. Zhang A. Costigan M. Yekkirala A. Barrett L. et al.Neuron. 2016; 89 (this issue): 956-970Abstract Full Text Full Text PDF Scopus (218) Google Scholar pursue a multi-level bioinformatics approach combined with wet bench validation to identify gene networks associated with the regenerative state of injured adult sensory neurons. A small molecular compound, ambroxol, mimics aspects of the identified gene expression patterns and promotes axon regeneration in the injured adult mouse CNS, demonstrating feasibility of in silico-based methods to identify compounds that promote neuronal growth following CNS injury. In higher vertebrates, including humans, the regenerative capacity of neurons in the injured adult central nervous system (CNS) is extremely limited. Accounts of spinal cord injury (SCI) and its treatment attempts date back to ancient times. The Greek physician Hippocrates of Kos (∼460–377 B.C.), considered the father of medicine and orthopedics, quite accurately noted: “There are no treatment options for spinal cord injury that resulted in paralysis, and unfortunately, those patients suffering from such injuries were destined to die.” While post-injury survival and surgical options for SCI patients have dramatically improved in recent years, moderate to severe CNS injury remains a serious medical challenge, with limited treatment options and a poor prognosis for complete recovery. In the spinal cord, traumatic injury of neural tissue typically results in an interruption of vital ascending and descending fiber tracts, causing a range of functional deficits. The long-term goal of SCI research is to develop strategies to ameliorate these deficits and improve, or fully restore, function. One key step toward accomplishing this ambitious goal is to re-establish neuronal innervation interrupted by SCI. Severed CNS axons typically show a modest and transient injury response that does not result in long-distance axonal regeneration. This stands in marked contrast to peripheral nervous system (PNS) injury, where sensory and motor axons can and often do regenerate over long distances, supporting substantial anatomical regeneration and functional recovery (Abe and Cavalli, 2008Abe N. Cavalli V. Curr. Opin. Neurobiol. 2008; 18: 276-283Crossref PubMed Scopus (210) Google Scholar). This dichotomy between PNS and CNS regeneration is, at least in part, the result of the growth-inhibitory nature of injured CNS tissue, first demonstrated by an elegant series of nerve transplantation experiments (Aguayo et al., 1978Aguayo A.J. Dickson R. Trecarten J. Attiwell M. Bray G.M. Richardson P. Neurosci. Lett. 1978; 9: 97-104Crossref PubMed Scopus (80) Google Scholar). Subsequent studies revealed that CNS myelin formed by mature oligodendrocytes contains many factors that potently inhibit growth and sprouting of severed axons (Winzeler et al., 2011Winzeler A.M. Mandemakers W.J. Sun M.Z. Stafford M. Phillips C.T. Barres B.A. J. Neurosci. 2011; 31: 6481-6492Crossref PubMed Scopus (68) Google Scholar, Fawcett et al., 2012Fawcett J.W. Schwab M.E. Montani L. Brazda N. Müller H.W. Handb. Clin. Neurol. 2012; 109: 503-522Crossref PubMed Scopus (103) Google Scholar, Schwab and Strittmatter, 2014Schwab M.E. Strittmatter S.M. Curr. Opin. Neurobiol. 2014; 27: 53-60Crossref PubMed Scopus (249) Google Scholar). To make matters worse, CNS axons are faced with additional obstacles; within days following injury, a glial scar composed of reactive astrocytes, microglia, and meningeal fibroblasts that migrate into the lesion site forms around the injury. Not only does scar tissue form a physical barrier to axonal regeneration, scar-associated molecules also function as chemical inhibitors that block axonal growth (Bradbury et al., 2002Bradbury E.J. Moon L.D. Popat R.J. King V.R. Bennett G.S. Patel P.N. Fawcett J.W. McMahon S.B. Nature. 2002; 416: 636-640Crossref PubMed Scopus (1896) Google Scholar, Busch and Silver, 2007Busch S.A. Silver J. Curr. Opin. Neurobiol. 2007; 17: 120-127Crossref PubMed Scopus (385) Google Scholar). Many of these growth-inhibitory molecules are either missing or greatly reduced in the injured PNS, providing clues for why axon regeneration in the CNS is more limited than in the PNS. While environmental (or extrinsic) constraints limit axonal growth, adult neurons, even when presented with a growth-permissive substrate, show greatly reduced axonal growth compared to their developing counterparts (Goldberg et al., 2002Goldberg J.L. Klassen M.P. Hua Y. Barres B.A. Science. 2002; 296: 1860-1864Crossref PubMed Scopus (376) Google Scholar). In other words, as neurons mature, cell-intrinsic programs that drive rapid axon extension during development go dormant and are incompletely activated following injury. Recent efforts to activate neuron-intrinsic growth programs have met with success and achieved impressive axonal regeneration in the injured optic nerve (Park et al., 2008Park K.K. Liu K. Hu Y. Smith P.D. Wang C. Cai B. Xu B. Connolly L. Kramvis I. Sahin M. He Z. Science. 2008; 322: 963-966Crossref PubMed Scopus (1152) Google Scholar, Moore et al., 2009Moore D.L. Blackmore M.G. Hu Y. Kaestner K.H. Bixby J.L. Lemmon V.P. Goldberg J.L. Science. 2009; 326: 298-301Crossref PubMed Scopus (520) Google Scholar, Benowitz et al., 2015Benowitz L.I. He Z. Goldberg J.L. Exp. Neurol. 2015; (Published online December 31, 2015)https://doi.org/10.1016/j.expneurol.2015.12.015Crossref Scopus (129) Google Scholar) and spinal cord (Liu et al., 2010Liu K. Lu Y. Lee J.K. Samara R. Willenberg R. Sears-Kraxberger I. Tedeschi A. Park K.K. Jin D. Cai B. et al.Nat. Neurosci. 2010; 13: 1075-1081Crossref PubMed Scopus (693) Google Scholar). Activation of the mTOR pathway combined with elevated Jak/STAT signaling leads to more impressive axonal regeneration than either treatment alone (Sun et al., 2011Sun F. Park K.K. Belin S. Wang D. Lu T. Chen G. Zhang K. Yeung C. Feng G. Yankner B.A. He Z. Nature. 2011; 480: 372-375Crossref PubMed Scopus (521) Google Scholar, Benowitz et al., 2015Benowitz L.I. He Z. Goldberg J.L. Exp. Neurol. 2015; (Published online December 31, 2015)https://doi.org/10.1016/j.expneurol.2015.12.015Crossref Scopus (129) Google Scholar). This suggests that multiple parallel pathways must be activated to achieve robust regeneration. The underlying gene networks that enable injured CNS neurons to extend long axons, however, remain poorly understood. In this issue of Neuron, Chandran et al., 2016Chandran V. Coppola G. Nawabi H. Omura T. Versano R. Huebner E.A. Zhang A. Costigan M. Yekkirala A. Barrett L. et al.Neuron. 2016; 89 (this issue): 956-970Abstract Full Text Full Text PDF Scopus (218) Google Scholar use an in silico approach combined with wet bench validation to discover transcriptional networks and their driver or “hub” genes associated with axon outgrowth in the PNS that are not recapitulated in the CNS. They go on to show that pharmacological activation of core elements of this transcriptional network is sufficient to elicit axonal regeneration in the injured adult mouse optic nerve. Sensory neurons in dorsal root ganglia (DRG) feature two long axons, one projecting peripherally and the other centrally to innervate the spinal cord or brainstem. Sensory signals originating from the lower limb travel through the sciatic nerve to the spinal cord, and they then extend into the medial part of the dorsal column where they travel rostrally to the gracile nucleus in the medulla oblongata. Severed DRG axons in the dorsal column do not regenerate spontaneously. However, a conditioning injury (CI) to the peripheral branch of DRG neurons, such as sciatic nerve crush injury, prior to dorsal column injury greatly enhances the regenerative capacity of the central branch (Richardson and Issa, 1984Richardson P.M. Issa V.M. Nature. 1984; 309: 791-793Crossref PubMed Scopus (407) Google Scholar). This seminal observation has been exploited by many investigators to uncover molecules, signaling pathways, and transcription factors that are regulated by CI, commonly referred to as regeneration-associated genes (RAGs) (Qiu et al., 2002Qiu J. Cai D. Dai H. McAtee M. Hoffman P.N. Bregman B.S. Filbin M.T. Neuron. 2002; 34: 895-903Abstract Full Text Full Text PDF PubMed Scopus (593) Google Scholar, Omura et al., 2015Omura T. Omura K. Tedeschi A. Riva P. Painter M.W. Rojas L. Martin J. Lisi V. Huebner E.A. Latremoliere A. et al.Neuron. 2015; 86: 1215-1227Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, Kwon et al., 2015Kwon M.J. Shin H.Y. Cui Y. Kim H. Thi A.H. Choi J.Y. Kim E.Y. Hwang D.H. Kim B.G. J. Neurosci. 2015; 35: 15934-15947Crossref Scopus (102) Google Scholar, Niemi et al., 2016Niemi J.P. DeFrancesco-Lisowitz A. Cregg J.M. Howarth M. Zigmond R.E. Exp. Neurol. 2016; 275: 25-37Crossref Scopus (58) Google Scholar). Overexpression of a single RAG alone is not sufficient to elicit significant neuronal growth, suggesting that combined activation of multiple RAGs may be needed for robust regeneration to occur. Over the past 10+ years, a large number of studies have examined how CI regulates gene expression in whole DRGs, including longitudinal studies examining transcriptional changes at different post-CI time points. Taking advantage of these existing datasets, gathered from a total of 382 microarrays, Chandran et al., 2016Chandran V. Coppola G. Nawabi H. Omura T. Versano R. Huebner E.A. Zhang A. Costigan M. Yekkirala A. Barrett L. et al.Neuron. 2016; 89 (this issue): 956-970Abstract Full Text Full Text PDF Scopus (218) Google Scholar performed weighted gene co-expression network analysis and identified gene networks and key signaling pathways regulated by CI. Combined with consensus network analysis, Chandran et al., 2016Chandran V. Coppola G. Nawabi H. Omura T. Versano R. Huebner E.A. Zhang A. Costigan M. Yekkirala A. Barrett L. et al.Neuron. 2016; 89 (this issue): 956-970Abstract Full Text Full Text PDF Scopus (218) Google Scholar identified hub genes and 14 co-expression modules preserved across independent nerve injury datasets, representing pathways associated with nerve regeneration. Focusing on significant module trait relationships, five regeneration-associated gene modules were identified, two modules with genes that are upregulated by CI and three with genes that are downregulated. Regulation of all five modules was found to be conserved in an independent dataset of peripheral nerve injury, providing confidence in this initial observation (Costigan et al., 2002Costigan M. Befort K. Karchewski L. Griffin R.S. D’Urso D. Allchorne A. Sitarski J. Mannion J.W. Pratt R.E. Woolf C.J. BMC Neurosci. 2002; 3: 16Crossref PubMed Scopus (456) Google Scholar). Perhaps the most difficult issue posed by this kind of database mining is prioritizing which of the many genes or gene networks associated with regeneration (or any biological process under investigation) should be selected for further experimentation. Faced with this challenge, Chandran et al., 2016Chandran V. Coppola G. Nawabi H. Omura T. Versano R. Huebner E.A. Zhang A. Costigan M. Yekkirala A. Barrett L. et al.Neuron. 2016; 89 (this issue): 956-970Abstract Full Text Full Text PDF Scopus (218) Google Scholar decided to examine each module for the presence of genes associated with axon regeneration, using PubMed as a reference followed by a Gene Ontology enrichment analysis to further annotate module function. As a step toward validation, the top 50 hub genes that represent the most central genes in all five regeneration modules identified above were compared to microarray datasets generated from injured CNS neurons lesioned by cervical SCI. Network relationships for two of the core modules were not preserved in CNS datasets, indicating that core PNS injury-related co-expression networks identified in DRG neurons are not preserved in injured neurons that fail to regenerate. To experimentally validate network-based predications about gene products associated with neuronal regeneration, 16 previously unidentified candidate RAGs were picked and assayed in primary neurons. In a first set of experiments, candidate RAGs were overexpressed in adult DRG neurons, and neurite outgrowth was quantified. Strikingly, 10 of the 16 RAGs tested showed a significant increase in neurite length and/or number. The top four genes (Fxyd5, Gfpt1, Smagp, and Tacstd2) were selected for shRNA-based loss-of-function studies in dissociated DRG neurons primed for enhanced neurite outgrowth by re-plating. For all genes examined, neurite outgrowth was significantly reduced compared to control shRNA-transduced DRG neurons, indicating their functional contribution to CI elicited growth effects. Therefore, Chandran et al., 2016Chandran V. Coppola G. Nawabi H. Omura T. Versano R. Huebner E.A. Zhang A. Costigan M. Yekkirala A. Barrett L. et al.Neuron. 2016; 89 (this issue): 956-970Abstract Full Text Full Text PDF Scopus (218) Google Scholar have identified several novel RAGs in DRG neurons that will need to be examined further, including functional regeneration studies in injured PNS and CNS neurons in vivo. Once regeneration gene modules are identified, a central question is understanding how they are regulated, since this could provide insight into how they might be globally controlled in the service of promoting regeneration. To this end, the authors chose to focus on the identification of transcription factors (TFs) that regulate co-expression of gene networks associated with axon regeneration. This was approached by scanning canonical promoter sequences in each RAG co-expression module for TF binding site enrichment. The scan identified a total of 62 significantly enriched TFs predicted to bind to promoters of regeneration genes examined, 39 of which had previously been confirmed by chromatin immunoprecipitation experiments. Strikingly, out of the five regeneration-associated modules originally identified, the two upregulated modules showed enrichment for TFs previously associated with axonal growth and neuronal injury response, including JUN, FOS, ATF3, EGR1, KLF4, STATs, SMAD, SP1, and SP2. While this finding provides confidence in this approach, it does not reveal insights into potential signaling pathways that may be controlled by the identified gene networks. To address this question, Chandran et al., 2016Chandran V. Coppola G. Nawabi H. Omura T. Versano R. Huebner E.A. Zhang A. Costigan M. Yekkirala A. Barrett L. et al.Neuron. 2016; 89 (this issue): 956-970Abstract Full Text Full Text PDF Scopus (218) Google Scholar used an in silico method to determine the protein-protein interaction (PPI) network in all five regeneration-associated modules. A relatively small network of interactions, consisting of 280 nodes and 496 edges, was identified. Interestingly, an enrichment in signaling pathways already implicated in neuronal regeneration was noted, including neurotrophin, MAP-kinase, TGFβ, chemokine, and Jak-STAT signaling pathways (Abe and Cavalli, 2008Abe N. Cavalli V. Curr. Opin. Neurobiol. 2008; 18: 276-283Crossref PubMed Scopus (210) Google Scholar). Thus, PPI not only provides independent validation of the relationships inferred by RNA co-expression, but it also reveals specific signaling pathways that may be targeted for therapeutic intervention following nervous system injury. Interestingly, there was a remarkable correspondence between TF binding site enrichment analysis in the RNA transcripts in co-expression modules and the hub genes identified in the PPI network. Moreover, many genes belonging to the enriched signaling pathways were also enriched for transcription factor binding sites of TFs in the PPI network. Collectively, these findings suggest that coordinate regulation of several regeneration-associated pathways may be necessary to achieve substantial neuronal growth and regeneration following injury. This also indicates that the identified TFs connect regeneration pathways, and their coordinate regulation is necessary for regeneration. This prediction was confirmed by bioinformatics removal of these TFs, resulting in disconnection of the network, leaving the distinct pathways unlinked. Importantly, the coordinate upregulation of these TFs is observed only in injured PNS neurons but not in injured CNS neurons, suggesting that differences in intrinsic gene expression patterns underlie the very different regenerative capacity of injured PNS and CNS neurons. While the regeneration gene module information uncovered thus far is of considerable interest, its value for promoting axonal growth in the injured CNS remains untested. One prediction is that injured CNS neurons convert from a non-regenerative state to an active growth state if TF networks critical for PNS neuron regeneration are activated in CNS neurons. This could be achieved by co-transfection and co-expression of multiple TFs. Such an endeavor appears rather ambitious, however, since not only the right doses of TFs but also their appropriate relative levels, posttranslational modifications, and nuclear translocation need to be achieved. Recognizing these limitations, Chandran et al., 2016Chandran V. Coppola G. Nawabi H. Omura T. Versano R. Huebner E.A. Zhang A. Costigan M. Yekkirala A. Barrett L. et al.Neuron. 2016; 89 (this issue): 956-970Abstract Full Text Full Text PDF Scopus (218) Google Scholar used a different approach, reasoning that if small molecules can be identified whose effects on gene expression in injured neurons approximate the core signaling networks identified in regenerating PNS neurons, such compounds should promote neurite outgrowth in non-primed PNS neurons, and perhaps also in injured CNS neurons. This would provide a strong proof of principle for the systems approach. So, next on the agenda was to find small molecules that mimic gene expression changes associated with axon regeneration. Chandran et al., 2016Chandran V. Coppola G. Nawabi H. Omura T. Versano R. Huebner E.A. Zhang A. Costigan M. Yekkirala A. Barrett L. et al.Neuron. 2016; 89 (this issue): 956-970Abstract Full Text Full Text PDF Scopus (218) Google Scholar compared changes in gene expression in the core PPI network with a publicly available database, called the Connectivity Map, harboring more than 7,000 expression profiles in non-neuronal cell lines for 1,309 compounds. The top three compounds best matching regeneration-associated gene expression were then tested for their ability to promote neurite outgrowth in vitro. One of them, called ambroxol, significantly enhanced axonal outgrowth in primary DRG neurons. Ambroxol blocks neuronal Na+ channels and is clinically used as a secretolytic agent for the treatment of certain respiratory diseases. In animal models ambroxol suppresses symptoms of neuropathic pain; however, its effect on PNS or CNS axon regeneration following nerve injury has not yet been examined. Gene expression analysis was performed to assess whether ambroxol targets candidate RAG regulatory networks in DRG neurons. Strikingly, DRG neurons showed a significant increase in core hub TFs (ATF3, FOS, JUN, SMAD1, and SP1) also present in the PPI network. These encouraging observations prompted a more direct evaluation of ambroxol in a CNS injury model. The optic nerve is part of the CNS, and following retro-orbital nerve injury, severed retinal ganglion cell axons exhibit a very limited regenerative response. To assess whether ambroxol promotes axon regeneration in the optic nerve, mice received an intra-ocular injection of ambroxol immediately before optic nerve injury and again at day 7 after injury; in addition, daily intra-peritoneal injections were performed until animals were sacrificed, 2 weeks after nerve injury. In mice treated with ambroxol, a mild but significantly increased regenerative response of severed retinal ganglion cell (RGC) axons was observed. The effect of ambroxol was enhanced when combined with shPTEN knockdown in RGCs, suggesting a synergistic effect with a known genetic manipulation that promotes CNS axon regeneration. Ambroxol is FDA approved, so can this drug be repurposed for applications in the setting of CNS injury? This appears unlikely, given its mild effect on injured RGCs. Also, studies in different CNS injury paradigms will need to be carried out to assess potential beneficial (or adverse) effects following SCI, traumatic brain injury, or stroke. Chandran et al., 2016Chandran V. Coppola G. Nawabi H. Omura T. Versano R. Huebner E.A. Zhang A. Costigan M. Yekkirala A. Barrett L. et al.Neuron. 2016; 89 (this issue): 956-970Abstract Full Text Full Text PDF Scopus (218) Google Scholar tested a single dose of ambroxol, starting treatment prior to nerve injury. Whether the regenerative phenotype observed in ambroxol-treated animals is due to co-expression of hub TFs in RGC neurons or is the result of more indirect effects involving glia or blood-derived immune cells has not yet been explored. Despite these limitations, this current work demonstrates the feasibility and predictive power of multi-level bioinformatics analyses to identify specific gene networks that regulate complex biological processes. Looking forward, this approach provides a foundation for a wide range of advances. Microarray datasets used by Chandran et al., 2016Chandran V. Coppola G. Nawabi H. Omura T. Versano R. Huebner E.A. Zhang A. Costigan M. Yekkirala A. Barrett L. et al.Neuron. 2016; 89 (this issue): 956-970Abstract Full Text Full Text PDF Scopus (218) Google Scholar were generated from whole ganglia rather than purified DRG neurons, and this could greatly increase the sensitivity of this sort of analysis. In addition to expression data from adult sensory neurons, the analysis may also be expanded by including transcriptomes of developing neurons, which are capable of very rapid axon extension, or even genetically manipulated adult CNS neurons in an active growth state. As more RNA-seq-based gene expression profiles for regenerating neurons become available, regeneration-associated changes in gene expression not currently detected by microarray, including coding and non-coding transcripts, will be revealed. Beyond gene expression profiling, in silico approaches are likely to expand to include epigenetic and post-transcriptional changes, including alterations in protein levels and post-translational modifications. There is no doubt that the number of drug-related gene expression profiles available through the Connectivity Map will continue to grow. In addition to expression data in non-neuronal cell lines, this will include drug-related gene expression profiles in neurons and other types of primary cells. Once available, this will set the stage to identify small molecular compounds, or combinations of compounds, that more accurately match gene expression changes observed in regenerating PNS neurons. This will likely identify compounds that are more powerful than ambroxol in promoting axonal regeneration and thus have the potential to be developed for neuronal repair applications. Lastly, despite the rapidly improving power of in silico methods to tackle complex biological processes, this current study underscores the need for predictions to be verified and scrutinized by wet bench experiments. Multi-level bioinformatics approaches augment but do not replace ongoing functional screens in model organisms or primary neurons, the work horses for discovering genes and pathways important for neuronal growth and regeneration; rather, in silico methods should be viewed as powerful new tools, opening new possibilities not fully realized by more conventional approaches. If fully integrated with wet bench approaches, this will accelerate drug discovery, enabling us to move more rapidly beyond the grim prognosis by Hippocrates for individuals with CNS injuries. A Systems-Level Analysis of the Peripheral Nerve Intrinsic Axonal Growth ProgramChandran et al.NeuronFebruary 18, 2016In BriefChandran et al. employ systems approaches to study PNS regenerative capacity after injury. They identify core networks and show that this program is observed after PNS, but not after CNS, injury. Utilizing networks, they identify a drug that promotes CNS regeneration. Full-Text PDF Open Archive" @default.
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• W2290464187 title "Inside Out: Core Network of Transcription Factors Drives Axon Regeneration" @default.
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