Contrasting the Glial Response to Axon Injury in the Central and Peripheral Nervous Systems
2014; Elsevier BV; Volume: 28; Issue: 1 Linguagem: Inglês
10.1016/j.devcel.2013.12.002
ISSN1878-1551
AutoresAmanda Brosius Lutz, Ben A. Barres,
Tópico(s)Axon Guidance and Neuronal Signaling
ResumoEnabling axon regeneration after central nervous system (CNS) injury remains a major challenge in neurobiology. One of the major differences between the injured peripheral nervous system (PNS) and CNS is the pro- and antiregenerative responses of their glial cell populations. In addition to intrinsic qualities of the neurons themselves, glial-driven changes to the neural environment have a significant impact on regenerative outcome. This Review presents a comparison of the glial response to injury between the CNS and PNS and highlights features of the PNS glial response that, with continued study, might reveal long-sought-after keys to achieving CNS repair. Enabling axon regeneration after central nervous system (CNS) injury remains a major challenge in neurobiology. One of the major differences between the injured peripheral nervous system (PNS) and CNS is the pro- and antiregenerative responses of their glial cell populations. In addition to intrinsic qualities of the neurons themselves, glial-driven changes to the neural environment have a significant impact on regenerative outcome. This Review presents a comparison of the glial response to injury between the CNS and PNS and highlights features of the PNS glial response that, with continued study, might reveal long-sought-after keys to achieving CNS repair. In higher vertebrates, peripheral nervous system (PNS) axons regenerate after injury while central nervous system (CNS) axons do not. This striking contrast in regenerative capacity is due to differences in the intrinsic properties of injured CNS and PNS neurons, as well as to differences in the CNS and PNS environments. Two major phenomena illustrate the contribution of intrinsic factors to CNS axon regeneration failure. First, mammalian CNS neurons regenerate their axons significantly faster during a perinatal window than just days or weeks later (Shimizu et al., 1990Shimizu I. Oppenheim R.W. 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Regeneration of dorsal column fibers into and beyond the lesion site following adult spinal cord injury.Neuron. 1999; 23: 83-91Abstract Full Text Full Text PDF PubMed Scopus (409) Google Scholar). These two observations have fueled the discovery in recent years of key growth-associated molecules, signaling pathways, and transcription factors that modulate a neuron's intrinsic capacity for axon growth, including GAP-43, cAMP, PTEN, mTOR, KLF4, and SOCS3. For a more complete discussion of intrinsic factors in CNS regeneration, readers are referred to excellent recent reviews of this topic (Liu et al., 2011Liu K. Tedeschi A. Park K.K. He Z. Neuronal intrinsic mechanisms of axon regeneration.Annu. Rev. Neurosci. 2011; 34: 131-152Crossref PubMed Scopus (163) Google Scholar, Sun and He, 2010Sun F. He Z. Neuronal intrinsic barriers for axon regeneration in the adult CNS.Curr. Opin. Neurobiol. 2010; 20: 510-518Crossref PubMed Scopus (98) Google Scholar). The stage for the discovery of specific environmental cues that influence axon regeneration was set by experiments conducted by David and Aguayo demonstrating that (1) peripheral neurons capable of regenerating over long distances in the PNS lose their ability to do so within the environment of a CNS nerve graft and, conversely, (2) the ability of numerous CNS neurons to regenerate is vastly enhanced within bridges of peripheral nerve tissue (Aguayo et al., 1981Aguayo A.J. David S. Bray G.M. Influences of the glial environment on the elongation of axons after injury: transplantation studies in adult rodents.J. Exp. Biol. 1981; 95: 231-240Crossref PubMed Google Scholar). Since these landmark studies, much progress has been made toward understanding the molecular basis for these observations. Several major components of the extracellular environment are now recognized to play important roles in axon regeneration. These extrinsic factors include extracellular matrix molecules, trophic factors, chemorepulsive guidance cues, and myelin-associated proteins and lipids. The composition of the CNS and PNS extracellular milieu is highly influenced by a class of nonneural, neurectoderm-derived cells known as glia. These cells, neuroepithelium-derived oligodendrocytes and astrocytes in the CNS and neural crest-derived Schwann cells in the PNS, outnumber their neural neighbors in humans and play key roles in creating both the growth-promoting environment of the injured PNS and the growth-inhibitory environment of the injured CNS (Allen and Barres, 2009Allen N.J. Barres B.A. Neuroscience: Glia - more than just brain glue.Nature. 2009; 457: 675-677Crossref PubMed Scopus (0) Google Scholar). The present Review focuses on the role of glia in nerve regeneration and aims to compare and contrast the contribution of CNS and PNS glia to five key elements of axon regeneration: neuronal survival, extracellular matrix composition, production and clearance of inhibitory myelin-associated proteins and lipids, and modulation of the inflammatory milieu. Although often referred to as distinct components of the axon growth equation, intrinsic and extrinsic growth cues are now recognized to be highly interconnected. For example, one of the direct consequences of intracellular cyclic AMP (cAMP) elevation is increased cell-surface localization of TrkB neurotrophin receptors, resulting in heightened neuronal responsiveness to extracellular neurotrophins (Meyer-Franke et al., 1998Meyer-Franke A. Wilkinson G.A. Kruttgen A. Hu M. Munro E. Hanson Jr., M.G. Reichardt L.F. Barres B.A. Depolarization and cAMP elevation rapidly recruit TrkB to the plasma membrane of CNS neurons.Neuron. 1998; 21: 681-693Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Liu et al., 2011Liu K. Tedeschi A. Park K.K. He Z. Neuronal intrinsic mechanisms of axon regeneration.Annu. Rev. Neurosci. 2011; 34: 131-152Crossref PubMed Scopus (163) Google Scholar). Similarly, we now know that a potent downstream effect of axon interaction with extracellular myelin debris involves intracellular activation of RhoA, rendering cytoskeletal dynamics unfavorable for axon extension (Yiu and He, 2006Yiu G. He Z. Glial inhibition of CNS axon regeneration.Nat. Rev. Neurosci. 2006; 7: 617-627Crossref PubMed Scopus (721) Google Scholar). A recent study by He and colleagues highlights the exciting therapeutic potential of targeting intrinsic factors. In this report, the authors demonstrate extensive and sustained axon regeneration in the optic nerve following concomitant deletion of genes PTEN and SOCS3 (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. Sustained axon regeneration induced by co-deletion of PTEN and SOCS3.Nature. 2011; 480: 372-375Crossref PubMed Scopus (215) Google Scholar). How manipulation of PTEN and SOCS3 signaling interfaces with pathways downstream of extrinsic inhibitory cues is an interesting ongoing area of study (Park et al., 2010Park K.K. Liu K. Hu Y. Kanter J.L. He Z. PTEN/mTOR and axon regeneration.Exp. Neurol. 2010; 223: 45-50Crossref PubMed Scopus (108) Google Scholar). It will also be interesting to see whether this regenerative phenotype can be further enhanced if coupled with strategies to dampen extrinsic inhibition. Indeed, as understanding of the connections between intracellular and extracellular pro- and antiregenerative cues deepens, the ultimate cellular consequences of extrinsic and intrinsic factors converge on a list of neuronal properties that appear to be important for axon regeneration. Key elements to date include the ability to retrogradely transport an injury signal to the cell soma, cell survival, an increase in de novo protein synthesis, anterograde transport of needed cellular constituents, favorable cytoskeletal dynamics, heightened responsiveness to trophic support, and downregulated responsiveness to inhibitory extracellular cues (Liu et al., 2011Liu K. Tedeschi A. Park K.K. He Z. Neuronal intrinsic mechanisms of axon regeneration.Annu. Rev. Neurosci. 2011; 34: 131-152Crossref PubMed Scopus (163) Google Scholar). As we shall see, the glial response to axon injury has a strong influence on several of these neuronal properties. Astrocytes are neuroepithelium-derived glia with finely branched processes found throughout the CNS. In the healthy CNS, astrocytes divide at a very low rate and provide several activities essential for neuronal function: they produce trophic support for neurons, perform homeostatic maintenance of the extracellular ionic environment and pH, clear and potentially release glutamate, provide metabolic substrates for neurons, couple cerebral blood flow to neuronal activity, and play a key role in synapse formation, maintenance, and function (Sofroniew, 2005Sofroniew M.V. Reactive astrocytes in neural repair and protection.Neuroscientist. 2005; 11: 400-407Crossref PubMed Scopus (391) Google Scholar, Eroglu and Barres, 2010Eroglu C. Barres B.A. Regulation of synaptic connectivity by glia.Nature. 2010; 468: 223-231Crossref PubMed Scopus (236) Google Scholar, Allen et al., 2012Allen N.J. Bennett M.L. Foo L.C. Wang G.X. Chakraborty C. Smith S.J. Barres B.A. Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors.Nature. 2012; 486: 410-414Crossref PubMed Scopus (8) Google Scholar). The mature astrocyte response to injury is a complex phenomenon termed "reactive gliosis," characterized by cellular hypertrophy, changes in gene expression, and cellular proliferation following particularly severe insults (Sofroniew, 2005Sofroniew M.V. Reactive astrocytes in neural repair and protection.Neuroscientist. 2005; 11: 400-407Crossref PubMed Scopus (391) Google Scholar, Sofroniew, 2009Sofroniew M.V. Molecular dissection of reactive astrogliosis and glial scar formation.Trends Neurosci. 2009; 32: 638-647Abstract Full Text Full Text PDF PubMed Scopus (823) Google Scholar). The specific stimuli that induce this response are still unknown, but degenerating axons and their dying terminals, serum-derived molecules at areas of blood-brain-barrier breakdown, and inflammation-associated cytokines have all been suggested to play an important role (Fitch and Silver, 2008Fitch M.T. Silver J. CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure.Exp. Neurol. 2008; 209: 294-301Crossref PubMed Scopus (0) Google Scholar). Elegant work over the past few years has begun to elucidate the molecular underpinnings of reactive gliosis and to examine its effects on astrocyte function (Wanner et al., 2013Wanner I.B. Anderson M.A. Song B. Levine J. Fernandez A. Gray-Thompson Z. Ao Y. Sofroniew M.V. Glial scar borders are formed by newly proliferated, elongated astrocytes that interact to corral inflammatory and fibrotic cells via STAT3-dependent mechanisms after spinal cord injury.J. 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Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice.Neuron. 1999; 23: 297-308Abstract Full Text Full Text PDF PubMed Scopus (541) Google Scholar). Certain aspects of this process will be discussed in detail below. Oligodendrocytes are also derived from the neuroepithelium and are the myelinating glia of the CNS. In humans, the period of myelination begins before birth and continues in some brain regions until 25–30 years of age (Fields, 2008Fields R.D. White matter in learning, cognition and psychiatric disorders.Trends Neurosci. 2008; 31: 361-370Abstract Full Text Full Text PDF PubMed Scopus (430) Google Scholar). Each oligodendrocyte extends processes that wrap numerous neighboring axons, with some forming a myelin internode on up to 50 axons. Although myelinating oligodendrocytes are postmitotic, a slowly dividing population of oligodendrocyte precursor cells (OPCs) persists in the adult brain (Kang et al., 2010Kang S.H. Fukaya M. Yang J.K. Rothstein J.D. Bergles D.E. NG2+ CNS glial progenitors remain committed to the oligodendrocyte lineage in postnatal life and following neurodegeneration.Neuron. 2010; 68: 668-681Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar, Fancy et al., 2011Fancy S.P. Chan J.R. Baranzini S.E. Franklin R.J. Rowitch D.H. Myelin regeneration: a recapitulation of development?.Annu. Rev. Neurosci. 2011; 34: 21-43Crossref PubMed Scopus (0) Google Scholar). In addition, new OPCs are generated from subventricular zone progenitors following injury (Fancy et al., 2011Fancy S.P. Chan J.R. Baranzini S.E. Franklin R.J. Rowitch D.H. Myelin regeneration: a recapitulation of development?.Annu. Rev. Neurosci. 2011; 34: 21-43Crossref PubMed Scopus (0) Google Scholar). One of the major differences between the CNS and the PNS is the proportion of myelinated versus unmyelinated fibers. In the CNS, nearly all white matter tracts are myelinated, whereas in the PNS, there are approximately four times as many unmyelinated axons as myelinated ones (Griffin and Thompson, 2008Griffin J.W. Thompson W.J. Biology and pathology of nonmyelinating Schwann cells.Glia. 2008; 56: 1518-1531Crossref PubMed Scopus (0) Google Scholar). All PNS axons are ensheathed by neural-crest-derived Schwann cells, which constitute over 80% of the cells in the adult peripheral nerve. According to axonal cues, these PNS glia differentiate during development into either nonmyelinating (Remak) Schwann cells or myelinating Schwann cells (Griffin and Thompson, 2008Griffin J.W. Thompson W.J. Biology and pathology of nonmyelinating Schwann cells.Glia. 2008; 56: 1518-1531Crossref PubMed Scopus (0) Google Scholar). In stark contrast to oligodendrocytes, myelinating Schwann cells form only one myelin internode around a single axon. Remak cells typically ensheath (without producing myelin) several axons, forming a Remak bundle. Schwann cells undergo a remarkable transformation in response to injury characterized by a transient period of proliferation and extensive changes in gene expression. Although many of the molecular changes result in a cellular state reminiscent of immature Schwann cells, recent work has determined the postinjury Schwann cell to be a unique repair cell poised to aid PNS regeneration with several features not found in earlier phases of the Schwann cell lineage (Arthur-Farraj et al., 2012Arthur-Farraj P.J. Latouche M. Wilton D.K. Quintes S. Chabrol E. Banerjee A. Woodhoo A. Jenkins B. Rahman M. Turmaine M. et al.c-Jun reprograms Schwann cells of injured nerves to generate a repair cell essential for regeneration.Neuron. 2012; 75: 633-647Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Furthermore, these studies have identified c-jun activation and upregulated Raf/Erk signaling as key regulators of the Schwann cell transformation (Arthur-Farraj et al., 2012Arthur-Farraj P.J. Latouche M. Wilton D.K. Quintes S. Chabrol E. Banerjee A. Woodhoo A. Jenkins B. Rahman M. Turmaine M. et al.c-Jun reprograms Schwann cells of injured nerves to generate a repair cell essential for regeneration.Neuron. 2012; 75: 633-647Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Napoli et al., 2012Napoli I. Noon L.A. Ribeiro S. Kerai A.P. Parrinello S. Rosenberg L.H. Collins M.J. Harrisingh M.C. White I.J. Woodhoo A. Lloyd A.C. A central role for the ERK-signaling pathway in controlling Schwann cell plasticity and peripheral nerve regeneration in vivo.Neuron. 2012; 73: 729-742Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). As the mechanisms of the Schwann cell response to injury are further elucidated, they may provide clues as to how to induce astrocytes and/or oligodendrocytes in the CNS to play a more productive role in nervous system repair. A recurring theme during neural development is the use of a limited supply of target-derived survival factors to match cell numbers to their targets (Oppenheim, 1989Oppenheim R.W. The neurotrophic theory and naturally occurring motoneuron death.Trends Neurosci. 1989; 12: 252-255Abstract Full Text PDF PubMed Scopus (0) Google Scholar). In the PNS, axon-derived type III neuregulin dictates Schwann cell survival during development, and in the current model of CNS development, oligodendrocytes compete for axon-derived cues for their survival as well (Barres and Raff, 1999Barres B.A. Raff M.C. Axonal control of oligodendrocyte development.J. Cell Biol. 1999; 147: 1123-1128Crossref PubMed Scopus (0) Google Scholar). If this scenario persisted into adulthood, axon degeneration distal to an injury would lead to widespread glial cell death. In the PNS, Schwann cell maturation is accompanied by the establishment of autocrine survival circuits involving PDGF, IGF-1, and NT3 (Jessen and Mirsky, 1999Jessen K.R. Mirsky R. Why do Schwann cells survive in the absence of axons?.Ann. N Y Acad. Sci. 1999; 883: 109-115Crossref PubMed Google Scholar). This mechanism ensures very little Schwann cell death after axon injury, allowing Schwann cells to play an active supportive role in PNS axon regeneration. However, following periods of chronic denervation lasting several months or more, increased Schwann cell death is ultimately observed (Ebenezer et al., 2007Ebenezer G.J. McArthur J.C. Thomas D. Murinson B. Hauer P. Polydefkis M. Griffin J.W. Denervation of skin in neuropathies: the sequence of axonal and Schwann cell changes in skin biopsies.Brain. 2007; 130: 2703-2714Crossref PubMed Scopus (0) Google Scholar). Studies of oligodendrocyte loss in adult compared with young rodents suggest that, like Schwann cells, dependence on axons for survival decreases with age (Barres and Raff, 1999Barres B.A. Raff M.C. Axonal control of oligodendrocyte development.J. Cell Biol. 1999; 147: 1123-1128Crossref PubMed Scopus (0) Google Scholar). Nonetheless, in stark contrast to the near-complete survival of Schwann cells in the injured PNS, rates of oligodendrocyte loss as high as 30%–40% are observed following axon injury in the mature CNS after months to years (Ludwin, 1990Ludwin S.K. Oligodendrocyte survival in Wallerian degeneration.Acta Neuropathol. 1990; 80: 184-191Crossref PubMed Scopus (0) Google Scholar). In addition to some degree of continued axon dependence, oligodendrocyte loss after CNS injury is attributed to excitotoxicity, inflammatory cytokine release by microglia and infiltrating neutrophils, and the exquisite vulnerability of these cells to oxidative stress from ischemia and reperfusion (Almad et al., 2011Almad A. Sahinkaya F.R. McTigue D.M. Oligodendrocyte fate after spinal cord injury.Neurotherapeutics. 2011; 8: 262-273Crossref PubMed Scopus (0) Google Scholar). Reported mechanisms of oligodendrocyte death include apoptosis, necrosis, and, most recently, autophagy (Almad et al., 2011Almad A. Sahinkaya F.R. McTigue D.M. Oligodendrocyte fate after spinal cord injury.Neurotherapeutics. 2011; 8: 262-273Crossref PubMed Scopus (0) Google Scholar). Surprisingly, the oligodendrocytes that survive injury appear to be of little utility in terms of CNS repair. These cells are described as inactive or quiescent and do not contribute to remyelination of spared axons (Ludwin, 1990Ludwin S.K. Oligodendrocyte survival in Wallerian degeneration.Acta Neuropathol. 1990; 80: 184-191Crossref PubMed Scopus (0) Google Scholar, Blakemore and Keirstead, 1999Blakemore W.F. Keirstead H.S. The origin of remyelinating cells in the central nervous system.J. Neuroimmunol. 1999; 98: 69-76Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Instead, oligodendrocyte precursor cells, either OPCs resident in the adult brain or OPCs derived from cortical subventricular zone precursors, differentiate into oligodendrocytes and perform successful remyelination (Blakemore and Keirstead, 1999Blakemore W.F. Keirstead H.S. The origin of remyelinating cells in the central nervous system.J. Neuroimmunol. 1999; 98: 69-76Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, Almad et al., 2011Almad A. Sahinkaya F.R. McTigue D.M. Oligodendrocyte fate after spinal cord injury.Neurotherapeutics. 2011; 8: 262-273Crossref PubMed Scopus (0) Google Scholar). Astrocytes survive CNS injury, but the signals required for their survival have long been mysterious. In recent work establishing a novel system for serum-free culture of mature astrocytes in vitro, Foo et al. found that endothelial cells, pericytes, and astrocytes themselves could promote astrocyte survival in culture. In addition, this work identified two molecules, heparin binding epidermal growth factor (HbEGF) and Wnt7a, as astrocyte survival factors and demonstrated elevated expression of HbEGF in brain endothelial cells. Based on these findings and consistent association of astrocyte endfeet with blood vessels in the mature brain, this study concludes that in addition to promoting their own survival, astrocytes in the healthy brain likely rely on vasculature-derived trophic support from endothelial cells and pericytes (Foo et al., 2011Foo L.C. Allen N.J. Bushong E.A. Ventura P.B. Chung W.S. Zhou L. Cahoy J.D. Daneman R. Zong H. Ellisman M.H. Barres B.A. Development of a method for the purification and culture of rodent astrocytes.Neuron. 2011; 71: 799-811Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar). Whether these same mechanisms act to keep astrocytes alive after injury has not been confirmed. Target-derived trophic support regulates neuronal survival during development, but what about after injury? Recent work presents evidence that a single transcription factor, dual leucine zipper kinase (DLK), primes the injured neuron for two possible responses to axon injury—apoptosis and regeneration—and that the path to go down is determined by the abundance of pro- or antiregenerative cues received by the neuron (Watkins et al., 2013Watkins T.A. Wang B. Huntwork-Rodriguez S. Yang J. Jiang Z. Eastham-Anderson J. Modrusan Z. Kaminker J.S. Tessier-Lavigne M. Lewcock J.W. DLK initiates a transcriptional program that couples apoptotic and regenerative responses to axonal injury.Proc. Natl. Acad. Sci. USA. 2013; 110: 4039-4044Crossref PubMed Scopus (63) Google Scholar). In line with this data, trophic factors have known effects on both neuronal survival and axon outgrowth. These factors bind to transmembrane receptors, typically tyrosine kinase receptors, and activate intracellular signaling pathways that inhibit apoptosis machinery from carrying out cell suicide. Two well-known pathways involved in trophic factor-mediated survival are the PI3-kinase/Akt pathway and the ras/raf/MAP kinase pathway (Goldberg and Barres, 2000Goldberg J.L. Barres B.A. The relationship between neuronal survival and regeneration.Annu. Rev. Neurosci. 2000; 23: 579-612Crossref PubMed Scopus (258) Google Scholar). The PI3-kinase/Akt pathway is upstream of GSK3-β and cytoskeletal arrangements favoring axon extension, perhaps explaining the dual effect of trophic support on neuronal survival and axon growth after injury (Chen et al., 2007Chen Z.L. Yu W.M. Strickland S. Peripheral regeneration.Annu. Rev. Neurosci. 2007; 30: 209-233Crossref PubMed Scopus (328) Google Scholar). Much like Schwann cells, mature PNS neurons are believed to decrease their dependence on target-derived trophic support and establish autocrine circuits to promote their own survival (Acheson et al., 1995Acheson A. Conover J.C. Fandl J.P. DeChiara T.M. Russell M. Thadani A. Squinto S.P. Yancopoulos G.D. Lindsay R.M. A BDNF autocrine loop in adult sensory neurons prevents cell death.Nature. 1995; 374: 450-453Crossref PubMed Google Scholar). After injury, Schwann cells provide an additional and important source of prosurvival factors for neurons. Schwann cells in the injured nerve upregulate numerous members of the neurotrophin family, including GDNF, Artemin, CNTF, LIF, BDNF, and NGF (Jessen and Mirsky, 2008Jessen K.R. Mirsky R. Negative regulation of myelination: relevance for development, injury, and demyelinating disease.Glia. 2008; 56: 1552-1565Crossref PubMed Scopus (0) Google Scholar, Arthur-Farraj et al., 2012Arthur-Farraj P.J. Latouche M. Wilton D.K. Quintes S. Chabrol E. Banerjee A. Woodhoo A. Jenkins B. Rahman M. Turmaine M. et al.c-Jun reprograms Schwann cells of injured nerves to generate a repair cell essential for regeneration.Neuron. 2012; 75: 633-647Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). The recent identification of regulators of the postinjury Schwann cell transformation has made it possible to examine neuron survival and axon regeneration in the absence of this transformation in vivo. A recent study accomplished this by deleting c-jun, a master regulator of the Schwann cell response to injury, specifically in Schwann cells. The authors observed dramatic increases in neuronal death as well as defects in axon regeneration, leading to the conclusion that injured mature peripheral nerves depend on c-jun-driven changes in Schwann cells in addition to autocrine signals for their survival (Arthur-Farraj et al., 2012Arthur-Farraj P.J. Latouche M. Wilton D.K. Quintes S. Chabrol E. Banerjee A. Woodhoo A. Jenkins B. Rahman M. Turmaine M. et al.c-Jun reprograms Schwann cells of injured nerves to generate a repair cell essential for regeneration.Neuron. 2012; 75: 633-647Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). In contrast to the high rates of neuronal survival in the injured PNS, poor neuronal survival after CNS injury is a major roadblock to regeneration. Work to date suggests that CNS neuron loss after injury results from a combination of loss of target-derived trophic support, loss of trophic factor responsiveness, and insufficient glial-derived trophic support (Goldberg and Barres, 2000Goldberg J.L. Barres B.A. The relationship between neuronal survival and regeneration.Annu. Rev. Neurosci. 2000; 23: 579-612Crossref PubMed Scopus (258) Google Scholar). Although trophic factors are produced by astrocytes after injury and astrocytes are sufficient to keep CNS neurons alive in culture, these factors are not present in the combinations and spatial and temporal gradients needed to support neuron survival in vivo (Banker, 1980Banker G.A. Trophic interactions between astroglial cells and hippocampal neurons in culture.Science. 1980; 209: 809-810Crossref PubMed Google Scholar, Goldberg and Barres, 2000Goldberg J.L. Barres B.A. The relationship between neuronal survival and regeneration.Annu. Rev. Neurosci. 2000; 23: 579-612Crossref PubMed Scopus (258) Google Scholar). One of the major differences between the CNS and PNS is the abundance of basal lamina. Schwann cells secrete a basal lamina composed of growth-promoting laminin, type IV collagen, and heparin sulfate proteoglycans (HSPGs), which is crucial to the ability of these cells to myelinate (Bunge et al., 1990Bunge M.B. Clark M.B. Dean A.C. Eldridge C.F. Bunge R.P. Schwann cell function depends upon axonal signals and basal lamina components.Ann. N Y Acad. Sci. 1990; 580: 281-287Crossref PubMed Scopus (0) Google Scholar). Interestingly, oligodendrocytes secrete no basal lamina, and, with the exception of the pial surface and places where astrocytes contact blood vessels, the healthy CNS is largely devoid of these molecules (Cornbrooks et al., 1983Cornbrooks C.J. Ca
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