Chunfeng Liu and Jinlian Liu contributed equally to this work.
Acta Biochimica et Biophysica Sinica, Volume 53, Issue 1, January 2021, Pages 1–9, https://doi.org/10.1093/abbs/gmaa148
23 December 2020 15 July 2020 Editorial decision: 07 September 2020 23 December 2020Chunfeng Liu, Jinlian Liu, Chaoqun Liu, Qing Zhou, Yaodong Zhou, Boyin Zhang, Saijilafu, The intrinsic axon regenerative properties of mature neurons after injury, Acta Biochimica et Biophysica Sinica, Volume 53, Issue 1, January 2021, Pages 1–9, https://doi.org/10.1093/abbs/gmaa148
Navbar Search Filter Mobile Enter search term Search Navbar Search Filter Enter search term SearchThousands of nerve injuries occur in the world each year. Axon regeneration is a very critical process for the restoration of the injured nervous system’s function. However, the precise molecular mechanism or signaling cascades that control axon regeneration are not clearly understood, especially in mammals. Therefore, there is almost no ideal treatment method to repair the nervous system’s injury until now. Mammalian axonal regeneration requires multiple signaling pathways to coordinately regulate gene expression in soma and assembly of the cytoskeleton protein in the growth cone. A better understanding of their molecular mechanisms, such as axon regeneration regulatory signaling cascades, will be helpful in developing new treatment strategies for promoting axon regeneration. In this review, we mainly focus on describing these regeneration-associated signaling cascades, which regulate axon regeneration.
Thousands of nerve injuries occur throughout the world as a result of trauma every year. Among them, axonal injury is a widespread problem in the neurological field. The connection between the neuron and its downstream targets may get disrupted due to axonal injury. This results in a complete loss of sensory, motor, and autonomic functions. Therefore, re-establishing neuronal circuits via promoting axon growth is an important issue for functional restoration. Although axon regeneration occurs in the peripheral nervous system (PNS) after injury, spontaneous axon growth is very limited in CNS. Researchers found that axons from the damaged spinal cord could grow into the grafted peripheral nerve segment [ 1]. Thus, the neuroscientists originally considered that neurons in CNS failed to regenerate mainly because of a hostile environment that does not support the axon growth [ 2–4]. Many studies in the past decade have largely focused on characterizing and blocking extrinsic inhibitory factors to promote axon growth. It has been reported that CNS will express various axon growth inhibitory factors after traumatic injuries, such as Nogo, MAG, and OMgp; these inhibitory factors often combine with the Nogo-66 receptor on the growth cone and activate the Rho–Rack signal pathway to induce the collapse of the growth cone via the actin–myosin system. However, a single or triple knockout of Nogo, MAG, and OMgp did not improve the inhibitory microenvironment of the injured CNS [ 5, 6]. Furthermore, in vivo axon regeneration in the spinal cord is still limited after antagonizing these inhibitory molecules. Additionally, neuroscientists further found that astrocytes in the damaged area of CNS will proliferate and secrete glial fibrillary acidic protein and chondroitin sulfate proteoglycans (CSPGs) to form glial scars, which is another major obstacle for axon regeneration. However, it is impossible to eliminate all inhibitory factors from the injured CNS, and a lack of one of the inhibitory molecules alone is not sufficient to enhance long-distance axonal regrowth in the injured mammalian CNS [ 7]. Thus, the strategy of promoting axon growth by blocking environmental inhibitors may not be an optical method. Another important reason why CNS neurons cannot regenerate axons after the injury is their diminished intrinsic axon growth capability. Therefore, scientists gradually shift their attention to promoting axon regeneration by manipulating the intrinsic axon growth abilities of neurons. It is well demonstrated that the mammalian CNS neurons lose their intrinsic axon regrowth ability during the developmental process. Previous studies revealed that embryonic retina ganglion cells could regrow their axons robustly after injury. However, their intrinsic axon growth ability is specifically lost during postnatal days P4–P5 [ 8]. During the normal developmental process, many intracellular signaling pathways spatiotemporally and coordinately regulate axon outgrowth. For example, neurotrophins, such as nerve growth factors and brain-derived neurotrophic factors (BDNFs), tightly regulate embryonic dorsal root ganglion (DRG) sensory axon growth via the extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3K). During the embryonic development, the PI3K pathway has been found to mainly regulate the local axon assembly by controlling actin polymerization via small GTPases and microtubule (MT) assembly via glycogen synthase kinase 3 (GSK3) at the growth cone. The ERK pathway mainly regulates genetic transcription in the soma via the activation of several transcription factors (TFs). Thus, it is possible that re-activation of these signaling cascades can restore mature CNS neurons to their previous embryonic status. On the other hand, a previous study demonstrated that some TFs, such as c-Myc, KLF4, STAT3, and SOCS3, would control the intrinsic axon growth ability of the optic nerve and/or corticospinal tract (CST). However, the connection or crosstalk between these well-recognized axon regeneration–associated genes (RAGs) is not fully understood. Identification of the signaling cascades associated with axonal regeneration and their subsequent downstream TFs will provide valuable information on how to promote axon regeneration in CNS by manipulating the intrinsic axon growth capacity of injured neurons. Furthermore, a better understanding of their molecular mechanisms, such as axon regeneration regulatory signaling cascades, will help develop new treatment strategies for promoting axon regeneration. Thus, in this review, we mainly focus on describing the regeneration-associated signaling cascades, which regulate axon regeneration in both invertebrates and mammals.
A simple organism, such as Caenorhabditis elegans or Drosophila, has been used as an excellent model for investigating the precise cellular and molecular mechanisms that control axon regeneration because of its relatively simple anatomical structure. Thus, promising progress has been obtained during the past decades in invertebrates using this excellent model to understand how cellular and molecular signaling pathways regulate axon regeneration. After an injury, many neurons in invertebrates regenerate axons robustly and spontaneously, fully re-establishing functional connection or neural circuits in some cases.
Axon injury in invertebrates such as C. elegans or Drosophila can activate many cross-linked signaling cascades such as the cyclic adenosine monophosphate (cAMP)–protein kinase A (PKA) pathway, the Jun N-terminal kinase (JNK) cascade, and dual leucine zipper kinase (DLK) 1–mitogen-activated protein (MAP) kinase pathway ( Fig. 1). These pathways are involved in the regeneration of axons by regulating cytoskeletal integrity, MT dynamics, and growth cone formation. After an injury, the axonal concentration of Ca 2+ is increased by several mechanisms, including an influx of extracellular calcium ions through the opened plasma membrane in C. elegans [ 5]. Then, the increased axonal Ca 2+ concentration further stimulates cAMP production by the activation of Ca 2+ -dependent enzymes such as adenylate cyclase [ 5]. Consistently, genetic elevation of axonal concentration of Ca 2+ or cAMP also promotes the growth cone formation of severed axons and subsequently axon regeneration via a PKA-dependent manner [ 5]. In contrast, a decrease in endogenous cAMP levels significantly reduces axonal regeneration [ 5]. Meanwhile, consistent with C. elegans, the PKA activity is also elevated in Drosophila s-LNv neurons, and the axon regeneration of the injured s-LNv neurons is significantly improved [ 6]. Thus, the effects of Ca 2+ and cAMP are mediated by PKA and may act as injury-triggered signals in invertebrate axon regeneration. In addition, the MAP kinase activity was also recently found to play important functional roles in the motor neuron regeneration in C. elegans [ 9, 10]. The DLK-1/PMK-3 MAP kinase signaling pathway is essential for axon regeneration and the normal growth cone formation. In Drosophila, axonal injury also activates Wallenda (Wnd, the Drosophila ortholog of DLK-1) signaling. Overexpression of Wnd in the larval nerve crush model is sufficient to protect axonal degeneration [ 11]. Additionally, the JNK cascade is another well-studied key signaling pathway that promotes axon regeneration in Drosophila [ 6]. JNK signaling is also upregulated in the fly brain injury model [ 12] as well as in the crushed larval ventral nerve cord model [ 11]. In the explanted fly brain, the activation of the JNK kinase [ 13] induces dramatic outgrowth of the severed axons, with one-third of them even extending to reenter the target area [ 6]. Furthermore, DLK-1 is upstream of the cellular autonomic damage signaling cascade involving JNK. Thus, Wnd/DLK kinase may regulate retrograde transport of injury signal to the soma ( Fig. 1). In the soma, it has been reported that axon injury activates the TFs KLF6/7 to regulate the axon RAG expression ( Fig. 1). Thus, axon regeneration of invertebrates is also intimately controlled by numerous signaling pathways. Using the genetic screening techniques, the scientists further found novel genes regulating axon regeneration in invertebrates [ 14, 15]. For example, it was found that the piwi-interacting RNA (piRNA) factors, PRDE-1 and PRG-1/PIWI, showed an inhibitory effect on axon regeneration in C. elegans [ 14]. Additional studies also revealed that the NAD + salvage pathway and the conserved Kelch-domain protein IVNS-1 inhibited axon growth [ 15]. Therefore, the study of axon regeneration in invertebrates could provide an insight into precise mechanisms that function in the injured mammalian nervous system.
Axon regeneration in invertebrates Axon injury-triggered Ca 2+ influx activates JNK signaling cascade and DLK signaling cascade and subsequently retrogradely transmits the injury signals to the soma. In the soma, the activation of KLF6/7 coordinately regulates the axon RAG expression.
Axonal regeneration in the injured mammalian nervous system is a very complex process compared with the invertebrates. Very little is known about the precise cellular and molecular mechanisms that control axon regeneration in the mammalian nervous system, especially in CNS. The mammalian CNS neurons usually lose their intrinsic axon regrowth ability during the developmental process. However, the mature neurons in the peripheral sensory nervous system can regain their ability to regenerate axons following traumatic injury spontaneously. The adult DRG neurons are an ideal experimental model for exploring the detailed molecular mechanisms of regulating mammalian natural axon regeneration after injury. DRG neurons possess a unipolar axon. Its axon is bifurcated into a peripheral branch and a spinal cord branch. Furthermore, the axons from the two branches of DRG neurons respond differently to the injury stimulus. Unlike the peripheral branch axons, which are robustly regenerated after injury, the axons in the spinal cord fail to regenerate following the injury. However, its regeneration in the spinal cord is greatly enhanced if the peripheral branch axon’s injury occurs before the spinal cord injury (SCI). This phenomenon is called the conditioning lesion effect [ 16]. It is believed that axon injury-induced activation of a regeneration program in the soma further increases the intrinsic axon regeneration capacity via a transcription-dependent mechanism in mammalian neurons [ 17]. However, its detailed molecular mechanisms are still rudimentary and fragmented.
Following injury, the neurons have to accurately and timely detect the injury signals to initiate regenerative programs that increase their intrinsic axon growth capacity. A potential reason for this issue is the retrograde transmission of injury signals to the soma from the lesion site ( Fig. 2). In other words, the locally elevated molecules by axon lesion convey the biological information to the soma and induce the upregulation of RAGs and subsequent increase of axon growth capacity. The influx of extracellular Ca 2+ also occurs in mammalian neurons after axonal injury [ 18]. A recent study also demonstrated that the DLK is involved in the injury signal’s retrograde transport of activating the DRG sensory neuronal intrinsic axon regeneration program in mice [ 19]. DLK is a mitogen-activated protein kinase kinase kinase that has been shown to activate JNK and p38 MAP kinase. Therefore, the phosphorylation of c-Jun in the DRG nuclei is completely blocked after sciatic nerve injury in the DLK-knockout mice. In addition, the retrograde transport of the JNK signaling component after peripheral nerve injury also contributes to the activation of c-Jun at the nucleus [ 20]. It has been reported that the AP-1 transcription factor c-Jun is required for axon regeneration [ 21, 22]. The lack of developmental axon growth defects in c-Jun null mice suggests that adult regenerating neurons may use different signaling pathways to regulate axon growth compared with embryonic neurons.
Cell body response after axon injury in mammals After axon injury, active gene transcription at the soma is essential to provide the raw materials for sustained axon growth. Thus far, many TFs and axon RAGs, such as Stat3, ATF3, PTEN, gap-43, and Sox11, were identified to regulate the mammalian axon regeneration. Better understanding the crosstalk between these axon regeneration-associated TFs or genes is of great importance to develop new therapeutic strategies for axon injury.
The classical PI3K signaling pathway was discovered to play important roles in nervous system development. For instance, neurotrophins such as NT-3 and BDNF regulate the axon growth during embryonic development by modulating glycogen synthase kinase 3β (GSK-3β) activity through the PI3K signaling pathway [ 23, 24]. However, our studies have demonstrated that the activation of PI3K signaling is necessary for condition lesion–induced axon regeneration of adult DRG neurons, which is significantly different from that of neurotrophin-induced developmental axon growth mode [ 17, 25]. The mutation of the catalytic subunit of PI3K p110δ also significantly impairs axon regeneration of adult DRG neurons [ 26]. Both adult neural axon regeneration and embryonic developmental axon growth mode, GSK3 inactivation was proved functionally necessary [ 27, 28]. As the direct target of the classical PI3K signaling pathway, Akt kinase regulates its downstream target GSK3 isoforms activity via N-terminal serine residue phosphorylation, such as the serine 21 (Ser 21) for GSK3α and serine 9 (Ser 9) for GSK3β [ 29]. Once these serine residues are phosphorylated by Akt kinase, GSK3 isoforms turn to an inactivation state, which lose the phosphorylation capacity. However, our published study clearly demonstrated that the GSK3 inactivation during axotomy-induced axon regeneration is independent of Akt-mediated phosphorylation [ 30]. Specifically, the peripheral axotomy-induced GSK3 inactivation and axon regeneration are unaffected in the GSK3 double knock-in mutant (GSK3α-Ser21A/GSKβ-S9A), which cannot be phosphorylated by Akt kinase.
Another possible mechanism contributing to injury-triggered activation of the intrinsic axon regeneration program is the interruption of target-derived growth stop signal by peripheral axotomy. During the nervous system development, growing axons stop elongating after reaching their targets and arborize in target fields to form synapses. Studies have shown that target-derived molecules such as Wnts and fibroblast growth factors (FGF) regulate synapse formation and maturation [ 31–33]. Thus, there is a possibility that such molecules may inhibit axon growth in association with the regulation of the formation of synapses.
Cell body responses, such as activating regeneration-associated TFs to ensure the synthesis of raw materials, are critically required to support continuous axon regeneration. However, in adult DRG sensory neurons, the transcription-dependent gene expressions are only found after the damage to the peripheral branches, but not after the central branches. Transcription initiation is closely controlled by a series of TFs and common factors, which mediate RNA polymerase binding to specific DNA regulatory factors—the contact region upstream of the transcription initiation site. It is important that the expression of these TFs and co-factors may coordinate the response of regenerating neurons after peripheral nerve injury. Early activation of a specific transcription pathway may be the first step required to mount the cell’s autonomic regeneration response. Studies have shown that many TFs including c-Jun, signal transducer and activator of transcription 3 (STAT3), activating TF 3 (ATF3), and Sox11 are activated in the DRG neurons immediately after peripheral axon injury [ 34–36]. Blocking these activated transcriptional programs reduces the axon regeneration ability of peripheral DRG neurons [ 17, 34]. Moore et al. [ 37] showed that the developmental regulation of Krüppel-like factor (KLF) underlies the loss of intrinsic axon growth capability of retina ganglion cell (RGC) neurons, and targeted deletion of the Klf4 gene in mouse retinal ganglion cells induces dramatic axon regeneration. The protein translation program in neuronal soma is another essential process for successful axon regeneration. Our published study showed that the inhibition of the general protein translation pathway with cycloheximide (5.0 μg/ml) completely blocks axon regeneration of cultured DRG neurons [ 34]. This result indicates that some protein synthesis in soma is also essential for axon regeneration. On the contrary, the activation of protein translation by deleting phosphate and tension homolog deleted on chromosome 10 (PTEN) gene also significantly increased axon regeneration of adult RGC neuron and cortical motor neurons via mammalian target of rapamycin (mTOR)-dependent protein translation pathway [ 38, 39]. Thus, the protein translation program in neuronal soma is sufficient to promote axon regeneration in mammals.
Additionally, the Smad family is a group of vital intracellular proteins that mediate signal transduction and regulate gene transcription. Recent research shows that conditioning lesion triggered the upregulation of Smad1, which turn injured sensory neurons into active conditions [ 40]. Once phosphorylated, Smad1 is retrogradely transported to soma and then enters the nucleus and regulates gene expression to promote axon growth. Our group’s recent study examined the regulatory mechanism of Smad1 in mature sensory axon regeneration [ 34]. Interestingly, we demonstrated that the expression of Smad1 in mature neurons was regulated by PI3K-GSK3β signaling rather than the well-entrenched BMP-Smad1 pathway. In addition, our in vitro culture-and-replating model revealed that the PI3K-GSK3β signaling mediates regrowth regulation specifically in the soma, but is not essential for cytoskeleton assembly in distal axons during axotomy-induced sensory axon regeneration. Therefore, the PI3K signaling may also regulate soma gene expression during mammalian natural axon regeneration [ 34].
The neuronal growth cone is a sensory-motile structure located at the tip of an extending axon, which is composed of a central domain rich in MTs and a peripheral domain enriched in actin filaments. The growth cone that controls the elongation rate and direction of nerve regeneration are highly specialized structures at the distal tips of axon. It is well known that axon elongation is an achievement of the cytoskeleton proteins and membrane components assembly at the nerve growth cone. Studies have demonstrated that local signaling at the growth cone also plays a pivotal role in axon regeneration ( Fig. 3). The growth cone is described in two regions: the peripheral domain (P domain) that consists of actin-based cytoskeleton and the central domain (C domain) that primarily comprises MT-based cytoskeleton. Change of the growth cone motility in the distribution of MTs and actin is a response to axon guidance cues. Dynamic MTs continuously extending from the C domain into the P domain is an important feature of an advancing growth cone, and microtubule-binding proteins (MBPs) are precisely coordinated MT dynamics. Many molecules were recently identified as MBPs, which specifically bind to the growing ends of the polymerizing MTs. For example, adenomatous polyposis coli (APC), end-binding proteins 1 and 3, cytoplasmic linker proteins, and cytoplasmic linker protein-associated proteins (CLASPs) function to regulate the extension or retraction of MT. There is increasing evidence suggesting intricate molecular interactions between these MBPs and other well-known axon growth regulators. GSK3, a multifunctional serine/threonine kinase, has been shown to regulate numerous MBP activity during axon regeneration, such as APC and collapsin response mediator protein 2 (CRMP2) and supports axon growth by regulating the stability of axonal MTs. Unlike other downstream candidates of GSK-3β, CRMP-2 is a primed substrate of GSK-3β, which requires prior phosphorylation near the GSK-3β catalytic sites by another priming kinase. As a crucial member of MBPs, CRMP-2 is enriched in the neural growth cone [ 41, 42]. Nonphosphorylated CRMP-2 binds to tubulin heterodimers to promote MT assembly, which results in axon elongation and branching [ 42]. By contrast, once phosphorylated by GSK-3β, CRMP-2 ruins the MT affinity blocking the MT polymerization and axon regeneration. Therefore, the neural growth cone structure and its cytoskeleton components provide the opportunity to orchestrate the axon regeneration effectively.
Cytoskeleton assembly at the growth cone during axon regeneration in mammals Successful axon elongation is an achievement of the cytoskeleton proteins and membrane components assembly at the nerve growth cone. The intricate molecular interactions between the MBPs and other well-known regulators of axon growth, such as GSK3 cascades, precisely control MT dynamics and its extension.
The gene expression of RAGs and the orchestration of cytoskeleton components are major determinants of axon regeneration capacity postinjury. However, the epigenetic pathway is another essential regulator of multiple genes activity during mammalian axon regeneration. It mainly controls the gene’s activity by histone modification, DNA methylation, and non-coding RNAs ( Fig. 4). In recent years, epigenetic regulations such as microRNA, histone modification, and DNA methylation have been found to play a crucial role in gene expression after nerve injury. First, some miRNAs have been revealed to have functions in the sensory axon regeneration in vitro and in vivo. Our published study provided the first evidence that miR-138 and histone deacetylase SIRT1 formed a mutual negative feedback loop to control peripheral sensory axon regeneration [ 43]. miR-26a also regulates PNS axon regeneration by downregulation of the GSK-3β activity [ 44]. As mentioned above, GSK-3β has been shown to control axonal growth by coordinating gene transcription, axonal transport, and local cytoskeleton assembly. In addition, emerging evidence further suggests that some global epigenetic regulators’ manipulations can promote postinjury axon regeneration in the CNS. For example, overexpression of histone acetyltransferase p300 can promote optic nerve axon regeneration [ 45]. Shin et al. [ 46] also found that the inhibition of histone deacetylase histone deacetylase 6 (HDAC6) could overcome the axon growth inhibitory effect of CSPG and MAG and promotes axon regeneration. In addition, overexpression of the nuclear active form of HDAC5 in RGCs also promotes its axon regeneration [ 47]. Thus, epigenetic regulations, especially histone modifications, effectively manipulate the regenerative capacity of the impaired axon by modulating RAG expression. MeCP2 is a methyl-CpG-binding protein which serves as an interpreter for DNA methylation modification. Recent study found that MeCP2 and cAMP response element binding (CREB) 1 form a positive transcription complex in CNS tissue during RAG transcription regulation [ 48]. H3K9 acetylation modification also plays an important role in RAG regulation. The peripheral nerve axotomy triggers an upregulation of permissive epigenetic marker H3K9ac and a downregulation of repressive epigenetic marker H3K9me2. Moreover, the H3K9ac was found to be enriched at the promoter regions of RAGs such as gap43, galanin, and BDNF [ 49]. Venkatesh et al. [ 50] reported that H3K4me3 was recruited at the promoter sites of RAGs during CNS development, such as gap43, sprr1a, integri-na7, and galanin. Nevertheless, the H3K4me3 enrichment at RAGs promoter sites was replaced by H3K27me3 after the embryo becomes mature. Consequently, the limitation of regeneration capacity of a mature axon is somewhat attributed to the restrain of RAGs gene expression of repressive epigenetic markers such as H3K27me3. Interestingly, cytoskeleton components of the neural growth cone can also be regulated by HDACs. Through MTs deacetylation, HDAC5 promotes the cytoskeleton dynamicity and promotes the neural growth cone assembly and axon regeneration [ 51]. Moreover, HDAC6 was discovered to modulate cytoskeleton remodeling in an actin-based manner [ 52].
The axon regeneration-associated epigenetic modifications in mammals Epigenetic modifications, such as histone or cytoskeleton acetylation, histone or DNA methylation, RNA-binding protein, and non-coding RNAs, were demonstrated to be closely related to the mammalian axon regeneration process. Understanding the underlying motivations behind these modifications is of great significance to unfold the molecular mechanisms of axon regeneration.
Due to the complexity of traumatic nerve injury, the clinical outcome and prognosis are notoriously difficult to predict. Therefore, an effective evaluation system to predict prognosis and estimate treatment principle is especially worthwhile to be established. Recently, multiple epigenetic-associated prognostic biomarkers were discovered from either cerebrospinal fluid or blood plasma [ 53]. Rodrigues et al. [ 54] reported that some epigenetic biomarker candidates are closely related to axon regeneration and cell survival after nerve injury. Nakanishi et al. [53] found the alternation of trauma-induced microRNA expression in the nervous system, such as the early stage of SCI. To be specific, the elevation of miR-223 expression was detected at 1 day post-SCI. By contrast, the miR-214a expression was profoundly decreased in 1 week post-SCI. In addition, the miR-9 level in peripheral blood was a potential forecaster for the SCI severity evaluation during the SCI acute phase [54]. The fluctuation in the expressions of these miRNAs post-SCI plays a crucial role in neuron survival and inflammatory activation. Although the bioinformatics significance behind the modification remains mysterious, these epigenetic biomarkers provide the possibility for SCI clinical intervention. Although the specific mechanism of axon regeneration-related epigenetic modification postinjury remains impenetrable, the epigenetic regulations undoubtedly provide a new strategy and feasible checkpoints for the study of axon regeneration after nerve injury.
Axon regeneration is an integral part of the successful function recovery after nerve injuries. Although much progress has been made to enhance axon regeneration by antagonizing these inhibitory molecules, in vivo axon regeneration in spinal cord is minimal. One important reason is that in vivo CNS regenerating axons usually encounter multiple inhibitory molecules simultaneously. As a result, removing one or a few inhibitory molecules cannot significantly promote axon regeneration due to the presence of other inhibitory molecules and potentially unidentified inhibitors. Therefore, targeting individual inhibitory molecules may not be the most effective way to promote axon regeneration in vivo. Recently emerging evidence suggests that regulation of the local cytoskeletal machinery in the growth cone can significantly enhance PNS axon regeneration. Thus, future studies may also be performed to test whether the manipulation of the growth cone cytoskeleton can enhance the regeneration of CNS axons in the brain or the spinal cord. Additionally, axonal regeneration in the injured mammalian nervous system is a very complex process that requires multiple signaling pathways to coordinately regulate gene expression and assembly of the cytoskeleton ( Table 1). Currently, the understanding of the precise cellular and molecular mechanisms underlying mature mammalian axonal regeneration is rudimentary. There are still many questions need to be answered. For example, how such axon regeneration-associated TFs are accurately activated after axon injury? How the genetic programs at the soma work in coordination with local signaling at the growth cone to regulate axon extension? There is an increasing body of evidence that clearly demonstrates that combinatorial approaches are necessary for successful axon regeneration, especially in the injured CNS. If successful, it will provide a potential new therapeutic strategy for axon regeneration both peripheral nerve injuries or SCIs and expend our knowledge of axon growth. We believe that following the increase of our understanding about the detailed molecular mechanisms of axon regeneration, the CNS injury, especially SCI, will become repairable.
Genes involved in the regulation of axon regeneration in mammals (↑: promotes axon growth; ↓: inhibits axon growth)
