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Neuronal maturation and axon regeneration: unfixing circuitry to enable repair

Abstract

Mammalian neurons lose the ability to regenerate their central nervous system axons as they mature during embryonic or early postnatal development. Neuronal maturation requires a transformation from a situation in which neuronal components grow and assemble to one in which these components are fixed and involved in the machinery for effective information transmission and computation. To regenerate after injury, neurons need to overcome this fixed state to reactivate their growth programme. A variety of intracellular processes involved in initiating or sustaining neuronal maturation, including the regulation of gene expression, cytoskeletal restructuring and shifts in intracellular trafficking, have been shown to prevent axon regeneration. Understanding these processes will contribute to the identification of targets to promote repair after injury or disease.

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Fig. 1: The transition from growth to stability during neuronal maturation.
Fig. 2: Genetic differences between immature and mature neurons affect axon regeneration.
Fig. 3: Intracellular trafficking in mature neurons excludes regeneration-associated molecules from the axon.
Fig. 4: Signalling changes during neuronal maturation restrict axon regeneration.
Fig. 5: Cytoskeletal dynamics orchestrating axon growth are shut down in mature neurons.

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References

  1. He, Z. & Jin, Y. Intrinsic control of axon regeneration. Neuron 90, 437–451 (2016).

    Article  CAS  PubMed  Google Scholar 

  2. Zheng, B. & Tuszynski, M. H. Regulation of axonal regeneration after mammalian spinal cord injury. Nat. Rev. Mol. Cell Biol. 24, 396–413 (2023).

    Article  CAS  PubMed  Google Scholar 

  3. Björklund, A. Long distance axonal growth in the adult central nervous system. J. Neurol. 242, S33–S35 (1994).

    Article  PubMed  Google Scholar 

  4. Lu, P. et al. Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell 150, 1264–1273 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Wang, X., Terman, J. & Martin, G. Regeneration of supraspinal axons after transection of the thoracic spinal cord in the developing opossum, Didelphis virginiana. J. Comp. Neurol. 398, 83–97 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Ruven, C. et al. Long-distance axon growth ability of corticospinal neurons is lost in a segmentally-distinct manner. Preprint in bioRxiv https://doi.org/10.1101/2022.03.20.484375 (2022). Using a novel microsurgical approach to lesion axons in the developing mouse, this preprint reports that neurons lose the ability to regenerate as they transition from elongating to arborizing axons during early postnatal development.

    Article  Google Scholar 

  7. Mahar, M. & Cavalli, V. Intrinsic mechanisms of neuronal axon regeneration. Nat. Rev. Neurosci. 19, 323–337 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Palmisano, I. & Di Giovanni, S. Advances and limitations of current epigenetic studies investigating mammalian axonal regeneration. Neurotherapeutics 15, 529–540 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Blanquie, O. & Bradke, F. Cytoskeleton dynamics in axon regeneration. Curr. Opin. Neurobiol. 51, 60–69 (2018).

    Article  CAS  PubMed  Google Scholar 

  10. Bradke, F., Di Giovanni, S. & Fawcett, J. Neuronal maturation: challenges and opportunities in a nascent field. Trends Neurosci. 43, 360–362 (2020).

    Article  CAS  PubMed  Google Scholar 

  11. Fawcett, J. W. The struggle to make CNS axons regenerate: why has it been so difficult? Neurochem. Res. 45, 144–158 (2020).

    Article  CAS  PubMed  Google Scholar 

  12. Hilton, B. J. et al. An active vesicle priming machinery suppresses axon regeneration upon adult CNS injury. Neuron 110, 51–69.e7 (2022). Core molecular components of the presynaptic active zone with a limited role in axon growth during neuronal development play a major role in preventing axon growth and regeneration in mature neurons.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hollville, E., Romero, S. E. & Deshmukh, M. Apoptotic cell death regulation in neurons. FEBS J. 286, 3276–3298 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Schelski, M. & Bradke, F. Neuronal polarization: from spatiotemporal signaling to cytoskeletal dynamics. Mol. Cell. Neurosci. 84, 11–28 (2017).

    Article  CAS  PubMed  Google Scholar 

  15. Coles, C. H. & Bradke, F. Coordinating neuronal actin–microtubule dynamics. Curr. Biol. 25, R677–R691 (2015).

    Article  CAS  PubMed  Google Scholar 

  16. Wallace, J. L. & Pollen, A. A. Human neuronal maturation comes of age: cellular mechanisms and species differences. Nat. Rev. Neurosci. 25, 7–29 (2023).

    Article  PubMed  Google Scholar 

  17. Bareyre, F. M. et al. The injured spinal cord spontaneously forms a new intraspinal circuit in adult rats. Nat. Neurosci. 7, 269 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Fouad, K., Pedersen, V., Schwab, M. E. & Brösamle, C. Cervical sprouting of corticospinal fibers after thoracic spinal cord injury accompanies shifts in evoked motor responses. Curr. Biol. 11, 1766–1770 (2001).

    Article  CAS  PubMed  Google Scholar 

  19. Li, Y. et al. Microglia-organized scar-free spinal cord repair in neonatal mice. Nature 587, 613–618 (2020). Neonatal microglia resolve inflammation by secreting peptidase inhibitors to prevent fibrotic scarring and enable robust repair following spinal cord injury.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Schwab, M. E. Functions of Nogo proteins and their receptors in the nervous system. Nat. Rev. Neurosci. 11, 799–811 (2010).

    Article  CAS  PubMed  Google Scholar 

  21. Vinopal, S. et al. Centrosomal microtubule nucleation regulates radial migration of projection neurons independently of polarization in the developing brain. Neuron 111, 1241–1263.e16 (2023). This study shows how the two interwoven dynamic processes — radial migration and axon growth — are separately controlled: by selective dependence of centrosomal and acentrosomal microtubule nucleation.

    Article  CAS  PubMed  Google Scholar 

  22. Luo, L. & O’Leary, D. D. Axon retraction and degeneration in development and disease. Annu. Rev. Neurosci. 28, 127–156 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. O’Leary, D. D. & Terashima, T. Cortical axons branch to multiple subcortical targets by interstitial axon budding: implications for target recognition and “waiting periods”. Neuron 1, 901–910 (1988).

    Article  PubMed  Google Scholar 

  24. Stanfield, B. B., O’Leary, D. D. & Fricks, C. Selective collateral elimination in early postnatal development restricts cortical distribution of rat pyramidal tract neurones. Nature 298, 371–373 (1982).

    Article  CAS  PubMed  Google Scholar 

  25. Südhof, T. C. Towards an understanding of synapse formation. Neuron 100, 276–293 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Südhof, T. C. The presynaptic active zone. Neuron 75, 11–25 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Washbourne, P. et al. Cell adhesion molecules in synapse formation. J. Neurosci. 24, 9244–9249 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Petanjek, Z. et al. Extraordinary neoteny of synaptic spines in the human prefrontal cortex. Proc. Natl Acad. Sci. USA 108, 13281–13286 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kano, M. & Hashimoto, K. Synapse elimination in the central nervous system. Curr. Opin. Neurobiol. 19, 154–161 (2009).

    Article  CAS  PubMed  Google Scholar 

  30. Kano, M. et al. Persistent multiple climbing fiber innervation of cerebellar purkinje cells in mice lacking mGluR1. Neuron 18, 71–79 (1997).

    Article  CAS  PubMed  Google Scholar 

  31. Caceres, A., Ye, B. & Dotti, C. G. Neuronal polarity: demarcation, growth and commitment. Curr. Opin. Cell Biol. 24, 547–553 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Haas, K. in Molecular Mechanisms of Synaptogenesis (eds Dityatev, A. & El-Husseini, A.) 297–309 (Springer, 2006).

  33. Ambrogini, P. et al. Morpho-functional characterization of neuronal cells at different stages of maturation in granule cell layer of adult rat dentate gyrus. Brain Res. 1017, 21–31 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Bean, B. P. The action potential in mammalian central neurons. Nat. Rev. Neurosci. 8, 451–465 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Atwood, H. L. & Karunanithi, S. Diversification of synaptic strength: presynaptic elements. Nat. Rev. Neurosci. 3, 497–516 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Canty, A. & Murphy, M. Molecular mechanisms of axon guidance in the developing corticospinal tract. Prog. Neurobiol. 85, 214–235 (2008).

    Article  CAS  PubMed  Google Scholar 

  37. Goldberg, J. L., Klassen, M. P., Hua, Y. & Barres, B. A. Amacrine-signaled loss of intrinsic axon growth ability by retinal ganglion cells. Science 296, 1860–1864 (2002).

    Article  CAS  PubMed  Google Scholar 

  38. Tedeschi, A. et al. The calcium channel subunit Alpha2delta2 suppresses axon regeneration in the adult CNS. Neuron 92, 419–434 (2016).

    Article  CAS  PubMed  Google Scholar 

  39. Kitao, Y., Robertson, B., Kudo, M. & Grant, G. Neurogenesis of subpopulations of rat lumbar dorsal root ganglion neurons including neurons projecting to the dorsal column nuclei. J. Comp. Neurol. 371, 249–257 (1996).

    Article  CAS  PubMed  Google Scholar 

  40. Sharma, N. et al. The emergence of transcriptional identity in somatosensory neurons. Nature 577, 392–398 (2020). This paper presents a transcriptomic atlas of the developing mouse dorsal root ganglion and shows that primary sensory neurons mature owing to the expression of subtype-restricted transcription factors in response to extrinsic cues.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Prasad, T. & Weiner, J. A. Direct and indirect regulation of spinal cord Ia afferent terminal formation by the γ-protocadherins. Front. Mol. Neurosci. 4, 54 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ramón y Cajal, S. Asociación método del nitrato de plata con el embrionario para el estudio de los focos motores y sensitivos. Trab. Lab. Invest. Biol. Univ. Madr. 3, 65–96 (1904).

    Google Scholar 

  43. Neumann, S. & Woolf, C. J. Regeneration of dorsal column fibers into and beyond the lesion site following adult spinal cord injury. Neuron 23, 83–91 (1999).

    Article  CAS  PubMed  Google Scholar 

  44. Ylera, B. et al. Chronically CNS-injured adult sensory neurons gain regenerative competence upon a lesion of their peripheral axon. Curr. Biol. 19, 930–936 (2009).

    Article  CAS  PubMed  Google Scholar 

  45. Richardson, P. & Issa, V. Peripheral injury enhances central regeneration of primary sensory neurones. Nature 309, 791–793 (1984).

    Article  CAS  PubMed  Google Scholar 

  46. Karimi-Abdolrezaee, S., Verge, V. M. & Schreyer, D. J. Developmental down-regulation of GAP-43 expression and timing of target contact in rat corticospinal neurons. Exp. Neurol. 176, 390–401 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Koseki, H. et al. Selective rab11 transport and the intrinsic regenerative ability of CNS axons. eLife 6, e26956 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Lorenzana, A. O., Lee, J. K., Mui, M., Chang, A. & Zheng, B. A surviving intact branch stabilizes remaining axon architecture after injury as revealed by in vivo imaging in the mouse spinal cord. Neuron 86, 947–954 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kim, H. et al. Oligodendrocyte precursor cells stop sensory axons regenerating into the spinal cord. Cell Rep. 42, 113068 (2023).

    Article  CAS  PubMed  Google Scholar 

  50. Filous, A. R. et al. Entrapment via synaptic-like connections between NG2 proteoglycan + cells and dystrophic axons in the lesion plays a role in regeneration failure after spinal cord injury. J. Neurosci. 34, 16369–16384 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Liu, K. et al. PTEN deletion enhances the regenerative ability of adult corticospinal neurons. Nat. Neurosci. 13, 1075–1081 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Enes, J. et al. Electrical activity suppresses axon growth through Cav1.2 channels in adult primary sensory neurons. Curr. Biol. 20, 1154–1164 (2010).

    Article  CAS  PubMed  Google Scholar 

  53. Eggermann, E., Bucurenciu, I., Goswami, S. P. & Jonas, P. Nanodomain coupling between Ca2+ channels and sensors of exocytosis at fast mammalian synapses. Nat. Rev. Neurosci. 13, 7–21 (2012).

    Article  CAS  Google Scholar 

  54. Calloway, N., Gouzer, G., Xue, M. & Ryan, T. A. The active-zone protein Munc13 controls the use-dependence of presynaptic voltage-gated calcium channels. eLife 4, e07728 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  55. Augustin, I., Rosenmund, C., Südhof, T. C. & Brose, N. Munc13-1 is essential for fusion competence of glutamatergic synaptic vesicles. Nature 400, 457–461 (1999).

    Article  CAS  PubMed  Google Scholar 

  56. van de Bospoort, R. et al. Munc13 controls the location and efficiency of dense-core vesicle release in neurons. J. Cell Biol. 199, 883–891 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Panayotis, N., Karpova, A., Kreutz, M. R. & Fainzilber, M. Macromolecular transport in synapse to nucleus communication. Trends Neurosci. 38, 108–116 (2015).

    Article  CAS  PubMed  Google Scholar 

  58. Hardingham, G. E., Fukunaga, Y. & Bading, H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat. Neurosci. 5, 405–414 (2002).

    Article  CAS  PubMed  Google Scholar 

  59. Herold, S., Jagasia, R., Merz, K., Wassmer, K. & Lie, D. C. CREB signalling regulates early survival, neuronal gene expression and morphological development in adult subventricular zone neurogenesis. Mol. Cell Neurosci. 46, 79–88 (2011).

    Article  CAS  PubMed  Google Scholar 

  60. Bloom, O. E. & Morgan, J. R. Membrane trafficking events underlying axon repair, growth, and regeneration. Mol. Cell. Neurosci. 48, 339–348 (2011).

    Article  CAS  PubMed  Google Scholar 

  61. Broeke, J. H. et al. Munc18 and Munc13 regulate early neurite outgrowth. Biol. Cell 102, 479–488 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Zhu, X.-H. et al. Quantitative imaging of energy expenditure in human brain. Neuroimage 60, 2107–2117 (2012).

    Article  PubMed  Google Scholar 

  63. Zhou, B. et al. Facilitation of axon regeneration by enhancing mitochondrial transport and rescuing energy deficits. J. Cell Biol. 214, 103–119 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Aprea, J. et al. Transcriptome sequencing during mouse brain development identifies long non‐coding RNAs functionally involved in neurogenic commitment. EMBO J. 32, 3145–3160 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Gallegos, D. A., Chan, U., Chen, L.-F. & West, A. E. Chromatin regulation of neuronal maturation and plasticity. Trends Neurosci. 41, 311–324 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Allshire, R. C. & Madhani, H. D. Ten principles of heterochromatin formation and function. Nat. Rev. Mol. Cell Biol. 19, 229–244 (2018).

    Article  CAS  PubMed  Google Scholar 

  67. Zhang, Y. et al. Overview of histone modification. Adv. Exp. Med. Biol. 1283, 1–16 (2021).

    Article  CAS  PubMed  Google Scholar 

  68. Guibert, S. & Weber, M. Functions of DNA methylation and hydroxymethylation in mammalian development. Curr. Top. Dev. Biol. 104, 47–83 (2013).

    Article  CAS  PubMed  Google Scholar 

  69. Yoo, A. S. & Crabtree, G. R. ATP-dependent chromatin remodeling in neural development. Curr. Opin. Neurobiol. 19, 120–126 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Venkatesh, I., Simpson, M. T., Coley, D. M. & Blackmore, M. G. Epigenetic profiling reveals a developmental decrease in promoter accessibility during cortical maturation in vivo. Neuroepigenetics 8, 19–26 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Wang, X.-W. et al. Histone methyltransferase Ezh2 coordinates mammalian axon regeneration via regulation of key regenerative pathways. J. Clin. Invest. 134, e163145 (2023). This paper demonstrates the importance of histone methylation in axon regeneration.

    Article  PubMed  Google Scholar 

  72. Renthal, W. et al. Transcriptional reprogramming of distinct peripheral sensory neuron subtypes after axonal injury. Neuron 108, 128–144.e9 (2020). Single-nucleus RNA sequencing demonstrates that peripheral axotomy of primary sensory neurons triggers reversible transcriptional reprogramming to enable axon regeneration.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Tetzlaff, W., Alexander, S. W., Miller, F. D. & Bisby, M. A. Response of facial and rubrospinal neurons to axotomy: changes in mRNA expression for cytoskeletal proteins and GAP-43. J. Neurosci. 11, 2528–2544 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Poplawski, G. H. et al. Injured adult neurons regress to an embryonic transcriptional growth state. Nature 581, 77–82 (2020). Gene expression profiling of corticospinal neurons following spinal cord injury reveals that mature neurons can upregulate the expression of regeneration-associated genes following axotomy but fail to sustain their expression.

    Article  CAS  PubMed  Google Scholar 

  75. Fernandes, K. J., Fan, D. P., Tsui, B., Cassar, S. & Tetzlaff, W. Influence of the axotomy to cell body distance in rat rubrospinal and spinal motoneurons: differential regulation of GAP‐43, tubulins, and neurofilament‐M. J. Comp. Neurol. 414, 495–510 (1999).

    Article  CAS  PubMed  Google Scholar 

  76. Wang, Z. et al. Injury distance limits the transcriptional response to spinal injury. Preprint at bioRxiv https://doi.org/10.1101/2024.05.27.596075 (2024).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Kim, H. J. et al. Deep scRNA sequencing reveals a broadly applicable Regeneration Classifier and implicates antioxidant response in corticospinal axon regeneration. Neuron 111, 3953–3969.e5 (2023). Single-cell sequencing (at high depth yet with a low throughput) of corticospinal neurons that regenerate due to genetic deletion of the tumour suppressor genes PTEN and SOCS3 establishes a role for antioxidant response in axon regeneration.

    Article  CAS  PubMed  Google Scholar 

  78. Moore, D. L. et al. KLF family members regulate intrinsic axon regeneration ability. Science 326, 298–301 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Norsworthy, M. W. et al. Sox11 expression promotes regeneration of some retinal ganglion cell types but kills others. Neuron 94, 1112–1120.e4 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Venkatesh, I., Mehra, V., Wang, Z., Califf, B. & Blackmore, M. G. Developmental chromatin restriction of ro‐growth gene networks acts as an epigenetic barrier to axon regeneration in cortical neurons. Dev. Neurobiol. 78, 960–977 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Deaton, A. M. & Bird, A. CpG islands and the regulation of transcription. Genes Dev. 25, 1010–1022 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Weng, Y.-L. et al. An intrinsic epigenetic barrier for functional axon regeneration. Neuron 94, 337–346.e6 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Loh, Y.-H. E. et al. Comprehensive mapping of 5-hydroxymethylcytosine epigenetic dynamics in axon regeneration. Epigenetics 12, 77–92 (2017).

    Article  PubMed  Google Scholar 

  84. Lu, Y. et al. Reprogramming to recover youthful epigenetic information and restore vision. Nature 588, 124–129 (2020). Overexpression of Yamanaka factors in mature retinal ganglion cell neurons elicits axon regeneration by reverting these neurons to a more youthful DNA methylation pattern.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Oh, Y. M. et al. Epigenetic regulator UHRF1 inactivates REST and growth suppressor gene expression via DNA methylation to promote axon regeneration. Proc. Natl Acad. Sci. USA 115, E12417–E12426 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Smith, J., Sen, S., Weeks, R. J., Eccles, M. R. & Chatterjee, A. Promoter DNA hypermethylation and paradoxical gene activation. Trends cancer 6, 392–406 (2020).

    Article  CAS  PubMed  Google Scholar 

  87. Reverdatto, S. et al. Developmental and injury-induced changes in DNA methylation in regenerative versus non-regenerative regions of the vertebrate central nervous system. BMC Genomics 23, 2 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Lindner, R., Puttagunta, R., Nguyen, T. & Di Giovanni, S. DNA methylation temporal profiling following peripheral versus central nervous system axotomy. Sci. Data 1, 140038 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Margueron, R. & Reinberg, D. The Polycomb complex PRC2 and its mark in life. Nature 469, 343–349 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Pereira, J. D. et al. Ezh2, the histone methyltransferase of PRC2, regulates the balance between self-renewal and differentiation in the cerebral cortex. Proc. Natl Acad. Sci. USA 107, 15957–15962 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Zhang, M. et al. Neuronal histone methyltransferase EZH2 regulates neuronal morphogenesis, synaptic plasticity, and cognitive behavior in mice. Neurosci. Bull. 39, 1512–1532 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Henriquez, B. et al. Ezh1 and Ezh2 differentially regulate PSD-95 gene transcription in developing hippocampal neurons. Mol. Cell. Neurosci. 57, 130–143 (2013).

    Article  CAS  PubMed  Google Scholar 

  93. Scimemi, A. Structure, function, and plasticity of GABA transporters. Front. Cell. Neurosci. 8, 161 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Habib, A. A. et al. Expression of the oligodendrocyte‐myelin glycoprotein by neurons in the mouse central nervous system. J. Neurochem. 70, 1704–1711 (1998).

    Article  CAS  PubMed  Google Scholar 

  95. Becker, T. et al. Tenascin‐R inhibits regrowth of optic fibers in vitro and persists in the optic nerve of mice after injury. Glia 29, 330–346 (2000).

    Article  CAS  PubMed  Google Scholar 

  96. Hollis, E. R. II Axon guidance molecules and neural circuit remodeling after spinal cord injury. Neurotherapeutics 13, 360–369 (2016).

    Article  PubMed  Google Scholar 

  97. Kim, J. et al. Polycomb-and methylation-independent roles of EZH2 as a transcription activator. Cell Rep. 25, 2808–2820.e4 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Laugesen, A., Højfeldt, J. W. & Helin, K. Molecular mechanisms directing PRC2 recruitment and H3K27 methylation. Mol. Cell 74, 8–18 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Jambhekar, A., Dhall, A. & Shi, Y. Roles and regulation of histone methylation in animal development. Nat. Rev. Mol. Cell Biol. 20, 625–641 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Shvedunova, M. & Akhtar, A. Modulation of cellular processes by histone and non-histone protein acetylation. Nat. Rev. Mol. Cell Biol. 23, 329–349 (2022).

    Article  CAS  PubMed  Google Scholar 

  101. Gräff, J. & Tsai, L.-H. Histone acetylation: molecular mnemonics on the chromatin. Nat. Rev. Neurosci. 14, 97–111 (2013).

    Article  PubMed  Google Scholar 

  102. Gaub, P. et al. HDAC inhibition promotes neuronal outgrowth and counteracts growth cone collapse through CBP/p300 and P/CAF-dependent p53 acetylation. Cell Death Differ. 17, 1392–1408 (2010).

    Article  CAS  PubMed  Google Scholar 

  103. Cho, Y., Sloutsky, R., Naegle, K. M. & Cavalli, V. Injury-induced HDAC5 nuclear export is essential for axon regeneration. Cell 155, 894–908 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Puttagunta, R. et al. PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system. Nat. Commun. 5, 3527 (2014).

    Article  PubMed  Google Scholar 

  105. Jiang, J. et al. MicroRNA-26a supports mammalian axon regeneration in vivo by suppressing GSK3β expression. Cell Death Dis. 6, e1865 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Wu, D. & Murashov, A. K. MicroRNA-431 regulates axon regeneration in mature sensory neurons by targeting the Wnt antagonist Kremen1. Front. Mol. Neurosci. 6, 35 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Liu, C.-M., Wang, R.-Y., Jiao, Z.-X., Zhang, B.-Y. & Zhou, F.-Q. MicroRNA-138 and SIRT1 form a mutual negative feedback loop to regulate mammalian axon regeneration. Genes Dev. 27, 1473–1483 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Kebede, A. F., Schneider, R. & Daujat, S. Novel types and sites of histone modifications emerge as players in the transcriptional regulation contest. FEBS J. 282, 1658–1674 (2015).

    Article  CAS  PubMed  Google Scholar 

  109. Richmond, S. et al. Localization of the glutamate receptor subunit GluR1 on the surface of living and within cultured hippocampal neurons. Neuroscience 75, 69–82 (1996).

    Article  CAS  PubMed  Google Scholar 

  110. Bradke, F. & Dotti, C. G. Neuronal polarity: vectorial cytoplasmic flow precedes axon formation. Neuron 19, 1175–1186 (1997).

    Article  CAS  PubMed  Google Scholar 

  111. Eva, R., Koseki, H., Kanamarlapudi, V. & Fawcett, J. W. EFA6 regulates selective polarised transport and axon regeneration from the axon initial segment. J. Cell Sci. 130, 3663–3675 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Rasband, M. N. The axon initial segment and the maintenance of neuronal polarity. Nat. Rev. Neurosci. 11, 552–562 (2010).

    Article  CAS  PubMed  Google Scholar 

  113. Yoshimura, T. & Rasband, M. N. Axon initial segments: diverse and dynamic neuronal compartments. Curr. Opin. Neurobiol. 27, 96–102 (2014).

    Article  CAS  PubMed  Google Scholar 

  114. Eichel, K. & Shen, K. The function of the axon initial segment in neuronal polarity. Dev. Biol. 489, 47–54 (2022).

    Article  CAS  PubMed  Google Scholar 

  115. Maeder, C. I., Shen, K. & Hoogenraad, C. C. Axon and dendritic trafficking. Curr. Opin. Neurobiol. 27, 165–170 (2014).

    Article  CAS  PubMed  Google Scholar 

  116. Villarroel‐Campos, D., Bronfman, F. C. & Gonzalez‐Billault, C. Rab GTPase signaling in neurite outgrowth and axon specification. Cytoskeleton 73, 498–507 (2016).

    Article  PubMed  Google Scholar 

  117. Britt, D. J., Farias, G. G., Guardia, C. M. & Bonifacino, J. S. Mechanisms of polarized organelle distribution in neurons. Front. Cell Neurosci. 10, 88 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Guedes-Dias, P. & Holzbaur, E. L. F. Axonal transport: driving synaptic function. Science 366, eaaw9997 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Gerges, N. Z., Backos, D. S. & Esteban, J. A. Local control of AMPA receptor trafficking at the postsynaptic terminal by a small GTPase of the Rab family. J. Biol. Chem. 279, 43870–43878 (2004).

    Article  CAS  PubMed  Google Scholar 

  120. Gonzalez-Gutierrez, A., Lazo, O. M. & Bronfman, F. C. The Rab5-Rab11 endosomal pathway is required for BDNF-induced CREB transcriptional regulation in hippocampal neurons. J. Neurosci. 40, 8042–8054 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Yap, C. C., Digilio, L., McMahon, L. P., Garcia, A. D. R. & Winckler, B. Degradation of dendritic cargos requires Rab7-dependent transport to somatic lysosomes. J. Cell Biol. 217, 3141–3159 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Petrova, V., Nieuwenhuis, B., Fawcett, J. W. & Eva, R. Axonal organelles as molecular platforms for axon growth and regeneration after injury. Int. J. Mol. Sci. 22, 1798 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Cheah, M. et al. Expression of an activated integrin promotes long-distance sensory axon regeneration in the spinal cord. J. Neurosci. 36, 7283–7297 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Yap, C. C. et al. The somatodendritic endosomal regulator NEEP21 facilitates axonal targeting of L1/NgCAM. J. Cell Biol. 180, 827–842 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Hollis, E. R., Jamshidi, P., Low, K., Blesch, A. & Tuszynski, M. H. Induction of corticospinal regeneration by lentiviral trkB-induced Erk activation. Proc. Natl Acad. Sci. USA 106, 7215–7220 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Duan, X. et al. Subtype-specific regeneration of retinal ganglion cells following axotomy: effects of osteopontin and mTOR signaling. Neuron 85, 1244–1256 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Maday, S. & Holzbaur, E. L. Autophagosome biogenesis in primary neurons follows an ordered and spatially regulated pathway. Dev. Cell 30, 71–85 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Nieuwenhuis, B. et al. PI 3-kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNS. EMBO Mol. Med. 12, e11674 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Petrova, V. et al. Protrudin functions from the endoplasmic reticulum to support axon regeneration in the adult CNS. Nat. Commun. 11, 5614 (2020). This paper demonstrates the importance of endoplasmic reticulum and associated proteins in axon regeneration.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Ferguson, S. M. Axonal transport and maturation of lysosomes. Curr. Opin. Neurobiol. 51, 45–51 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Devine, M. J. & Kittler, J. T. Mitochondria at the neuronal presynapse in health and disease. Nat. Rev. Neurosci. 19, 63–80 (2018).

    Article  CAS  PubMed  Google Scholar 

  132. Cheng, X. T. & Sheng, Z. H. Developmental regulation of microtubule-based trafficking and anchoring of axonal mitochondria in health and diseases. Dev. Neurobiol. 81, 284–299 (2021).

    Article  PubMed  Google Scholar 

  133. Andrews, M. R. et al. Axonal localization of integrins in the CNS is neuronal type and age dependent. eNeuro 3, ENEURO.0029-16.2016 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Franssen, E. H. et al. Exclusion of integrins from CNS axons is regulated by Arf6 activation and the AIS. J. Neurosci. 35, 8359–8375 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Montagnac, G. et al. ARF6 Interacts with JIP4 to control a motor switch mechanism regulating endosome traffic in cytokinesis. Curr. Biol. 19, 184–195 (2009).

    Article  CAS  PubMed  Google Scholar 

  136. Werner, A. et al. Impaired axonal regeneration in α7 integrin-deficient mice. J. Neurosci. 20, 1822–1830 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Hight-Warburton, W. & Parsons, M. Regulation of cell migration by α4 and α9 integrins. Biochem. J. 476, 705–718 (2019).

    Article  CAS  PubMed  Google Scholar 

  138. Cheah, M. et al. Integrin-driven axon regeneration in the spinal cord activates a distinctive CNS regeneration program. J. Neurosci. 43, 4775–4794 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Anderson, M. A. et al. Required growth facilitators propel axon regeneration across complete spinal cord injury. Nature 561, 396–400 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Santos, T. E. et al. Axon growth of CNS neurons in three dimensions is amoeboid and independent of adhesions. Cell Rep. 32, 107907 (2020). This paper challenges the classical concept of how CNS axons grow: not pulling with their growth cones on the substrate to move themselves forward but rather through an amoeboid movement, where microtubules protrude further distally.

    Article  CAS  PubMed  Google Scholar 

  141. Witte, H., Neukirchen, D. & Bradke, F. Microtubule stabilization specifies initial neuronal polarization. J. Cell Biol. 180, 619–632 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Kamiguchi, H. The role of cell adhesion molecules in axon growth and guidance. Adv. Exp. Med. Biol. 621, 95–103 (2007).

    Article  PubMed  Google Scholar 

  143. Haspel, J. et al. Critical and optimal Ig domains for promotion of neurite outgrowth by L1/Ng-CAM. J. Neurobiol. 42, 287–302 (2000).

    Article  CAS  PubMed  Google Scholar 

  144. Maness, P. F. & Schachner, M. Neural recognition molecules of the immunoglobulin superfamily: signaling transducers of axon guidance and neuronal migration. Nat. Neurosci. 10, 19–26 (2007).

    Article  CAS  PubMed  Google Scholar 

  145. Chen, J. et al. Adeno-associated virus-mediated L1 expression promotes functional recovery after spinal cord injury. Brain 130, 954–969 (2007).

    Article  PubMed  Google Scholar 

  146. Verma, P. et al. Axonal protein synthesis and degradation are necessary for efficient growth cone regeneration. J. Neurosci. 25, 331–342 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Hanz, S. et al. Axoplasmic importins enable retrograde injury signaling in lesioned nerve. Neuron 40, 1095–1104 (2003).

    Article  CAS  PubMed  Google Scholar 

  148. Holt, C. E. & Schuman, E. M. The central dogma decentralized: new perspectives on RNA function and local translation in neurons. Neuron 80, 648–657 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Bourke, A. M., Schwarz, A. & Schuman, E. M. De-centralizing the central dogma: mRNA translation in space and time. Mol. Cell 83, 452–468 (2023).

    Article  CAS  PubMed  Google Scholar 

  150. Costa, R. O. et al. Synaptogenesis stimulates a proteasome-mediated ribosome reduction in axons. Cell Rep. 28, 864–876.e6 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Kim, E. & Jung, H. Local mRNA translation in long-term maintenance of axon health and function. Curr. Opin. Neurobiol. 63, 15–22 (2020).

    Article  CAS  PubMed  Google Scholar 

  152. Dalla Costa, I. et al. The functional organization of axonal mRNA transport and translation. Nat. Rev. Neurosci. 22, 77–91 (2021).

    Article  CAS  PubMed  Google Scholar 

  153. Luarte, A., Cornejo, V. H., Bertin, F., Gallardo, J. & Couve, A. The axonal endoplasmic reticulum: one organelle-many functions in development, maintenance, and plasticity. Dev. Neurobiol. 78, 181–208 (2018).

    Article  CAS  PubMed  Google Scholar 

  154. Yalcin, B. et al. Modeling of axonal endoplasmic reticulum network by spastic paraplegia proteins. eLife 6, e23882 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  155. Rao, K. et al. Spastin, atlastin, and ER relocalization are involved in axon but not dendrite regeneration. Mol. Biol. Cell 27, 3245–3256 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Farias, G. G. et al. Feedback-driven mechanisms between microtubules and the endoplasmic reticulum instruct neuronal polarity. Neuron 102, 184–201.e8 (2019).

    Article  CAS  PubMed  Google Scholar 

  157. Kurowska, Z., Brundin, P., Schwab, M. E. & Li, J. Y. Intracellular Nogo-A facilitates initiation of neurite formation in mouse midbrain neurons in vitro. Neuroscience 256, 456–466 (2014).

    Article  CAS  PubMed  Google Scholar 

  158. Cartoni, R., Pekkurnaz, G., Wang, C., Schwarz, T. L. & He, Z. A high mitochondrial transport rate characterizes CNS neurons with high axonal regeneration capacity. PLoS One 12, e0184672 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  159. Cartoni, R. et al. The mammalian-specific protein Armcx1 regulates mitochondrial transport during axon regeneration. Neuron 92, 1294–1307 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Han, Q. et al. Restoring cellular energetics promotes axonal regeneration and functional recovery after spinal cord injury. Cell Metab. 31, 623–641.e8 (2020). Removing an anchor on mitochondria that becomes active as neurons mature enhances mitochondrial transport and enables corticospinal regeneration following CNS injury.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Govek, E.-E., Newey, S. E. & Van Aelst, L. The role of the Rho GTPases in neuronal development. Genes Dev. 19, 1–49 (2005).

    Article  CAS  PubMed  Google Scholar 

  162. Rosenberg, S. S. & Spitzer, N. C. Calcium signaling in neuronal development. Cold Spring Harb. Perspect. Biol. 3, a004259 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  163. Sánchez-Alegría, K., Flores-León, M., Avila-Muñoz, E., Rodríguez-Corona, N. & Arias, C. PI3K signaling in neurons: a central node for the control of multiple functions. Int. J. Mol. Sci. 19, 3725 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  164. Garvalov, B. K. et al. Cdc42 regulates cofilin during the establishment of neuronal polarity. J. Neurosci. 27, 13117–13129 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Tahirovic, S. et al. Rac1 regulates neuronal polarization through the WAVE complex. J. Neurosci. 30, 6930–6943 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Dupraz, S. et al. RhoA controls axon extension independent of specification in the developing brain. Curr. Biol. 29, 3874–3886.e9 (2019).

    Article  CAS  PubMed  Google Scholar 

  167. Ng, J. & Luo, L. Rho GTPases regulate axon growth through convergent and divergent signaling pathways. Neuron 44, 779–793 (2004).

    Article  CAS  PubMed  Google Scholar 

  168. West, A. E., Griffith, E. C. & Greenberg, M. E. Regulation of transcription factors by neuronal activity. Nat. Rev. Neurosci. 3, 921–931 (2002).

    Article  CAS  PubMed  Google Scholar 

  169. Hausser, M., Spruston, N. & Stuart, G. J. Diversity and dynamics of dendritic signaling. Science 290, 739–744 (2000).

    Article  CAS  PubMed  Google Scholar 

  170. Thomas, G. M. & Huganir, R. L. MAPK cascade signalling and synaptic plasticity. Nat. Rev. Neurosci. 5, 173–183 (2004).

    Article  CAS  PubMed  Google Scholar 

  171. Kennedy, M. B. Synaptic signaling in learning and memory. Cold Spring Harb. Perspect. Biol. 8, a016824 (2016).

    Article  PubMed Central  Google Scholar 

  172. Czech, M. P. PIP2 and PIP3: complex roles at the cell surface. Cell 100, 603–606 (2000).

    Article  CAS  PubMed  Google Scholar 

  173. Park, K. K. et al. Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science 322, 963–966 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Geoffroy, C. G., Hilton, B. J., Tetzlaff, W. & Zheng, B. Evidence for an age-dependent decline in axon regeneration in the adult mammalian central nervous system. Cell Rep. 15, 238–246 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Du, K. et al. Pten deletion promotes regrowth of corticospinal tract axons 1 year after spinal cord injury. J. Neurosci. 35, 9754–9763 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Lewandowski, G. & Steward, O. AAVshRNA-mediated suppression of PTEN in adult rats in combination with salmon fibrin administration enables regenerative growth of corticospinal axons and enhances recovery of voluntary motor function after cervical spinal cord injury. J. Neurosci. 34, 9951–9962 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  177. Hammarlund, M., Nix, P., Hauth, L., Jorgensen, E. M. & Bastiani, M. Axon regeneration requires a conserved MAP kinase pathway. Science 323, 802–806 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Chen, L. et al. Axon regeneration pathways identified by systematic genetic screening in C. elegans. Neuron 71, 1043–1057 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Shin, J. E. et al. Dual leucine zipper kinase is required for retrograde injury signaling and axonal regeneration. Neuron 74, 1015–1022 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Watkins, T. A. et al. DLK initiates a transcriptional program that couples apoptotic and regenerative responses to axonal injury. Proc. Natl Acad. Sci. USA 110, 4039–4044 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Saikia, J. M. et al. A critical role for DLK and LZK in axonal repair in the mammalian spinal cord. J. Neurosci. 42, 3716–3732 (2022). Two kinases implicated in retrograde injury signalling, DLK and LZK, have redundant roles in promoting axon regeneration and compensatory sprouting following axonal injury in the mature mammalian CNS.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Hannila, S. S. & Filbin, M. T. The role of cyclic AMP signaling in promoting axonal regeneration after spinal cord injury. Exp. Neurol. 209, 321–332 (2008).

    Article  CAS  PubMed  Google Scholar 

  183. Qiu, J. et al. Spinal axon regeneration induced by elevation of cyclic AMP. Neuron 34, 895–903 (2002).

    Article  CAS  PubMed  Google Scholar 

  184. Neumann, S., Bradke, F., Tessier-Lavigne, M. & Basbaum, A. I. Regeneration of sensory axons within the injured spinal cord induced by intraganglionic cAMP elevation. Neuron 34, 885–893 (2002).

    Article  CAS  PubMed  Google Scholar 

  185. Gao, Y. et al. Activated CREB is sufficient to overcome inhibitors in myelin and promote spinal axon regeneration in vivo. Neuron 44, 609–621 (2004).

    Article  CAS  PubMed  Google Scholar 

  186. Chierzi, S., Ratto, G. M., Verma, P. & Fawcett, J. W. The ability of axons to regenerate their growth cones depends on axonal type and age, and is regulated by calcium, cAMP and ERK. Eur. J. Neurosci. 21, 2051–2062 (2005).

    Article  PubMed  Google Scholar 

  187. Flynn, K. C. et al. ADF/cofilin-mediated actin retrograde flow directs neurite formation in the developing brain. Neuron 76, 1091–1107 (2012).

    Article  CAS  PubMed  Google Scholar 

  188. Tomasek, J. J., Haaksma, C. J., Eddy, R. J. & Vaughan, M. B. Fibroblast contraction occurs on release of tension in attached collagen lattices: dependency on an organized actin cytoskeleton and serum. Anat. Rec. 232, 359–368 (1992).

    Article  CAS  PubMed  Google Scholar 

  189. Bradke, F. & Dotti, C. G. The role of local actin instability in axon formation. Science 283, 1931–1934 (1999).

    Article  CAS  PubMed  Google Scholar 

  190. Schelski, M. & Bradke, F. Microtubule retrograde flow retains neuronal polarization in a fluctuating state. Sci. Adv. 8, eabo2336 (2022). This paper and Burute et al.191 showed that the microtubule array of neurites of developing neurons is not a steady structure: they flow constantly in a retrograde direction back to the cell body.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Burute, M., Jansen, K. I., Mihajlovic, M., Vermonden, T. & Kapitein, L. C. Local changes in microtubule network mobility instruct neuronal polarization and axon specification. Sci. Adv. 8, eabo2343 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Stiess, M. et al. Axon extension occurs independently of centrosomal microtubule nucleation. Science 327, 704–707 (2010).

    Article  CAS  PubMed  Google Scholar 

  193. Erez, H. et al. Formation of microtubule-based traps controls the sorting and concentration of vesicles to restricted sites of regenerating neurons after axotomy. J. Cell Biol. 176, 497–507 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Ertürk, A., Hellal, F., Enes, J. & Bradke, F. Disorganized microtubules underlie the formation of retraction bulbs and the failure of axonal regeneration. J. Neurosci. 27, 9169–9180 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  195. Ruschel, J. et al. Systemic administration of epothilone B promotes axon regeneration after spinal cord injury. Science 348, 347–352 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Hellal, F. et al. Microtubule stabilization reduces scarring and causes axon regeneration after spinal cord injury. Science 331, 928–931 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Griffin, J. M. et al. Rehabilitation enhances epothilone-induced locomotor recovery after spinal cord injury. Brain Commun. 5, fcad005 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  198. Ruschel, J. & Bradke, F. Systemic administration of epothilone D improves functional recovery of walking after rat spinal cord contusion injury. Exp. Neurol. 306, 243–249 (2018).

    Article  CAS  PubMed  Google Scholar 

  199. O’Shea, T. M., Burda, J. E. & Sofroniew, M. V. Cell biology of spinal cord injury and repair. J. Clin. Invest. 127, 3259–3270 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  200. Dent, E. W. Dynamic microtubules at the synapse. Curr. Opin. Neurobiol. 63, 9–14 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Guedes-Dias, P. et al. Kinesin-3 responds to local microtubule dynamics to target synaptic cargo delivery to the presynapse. Curr. Biol. 29, 268–282.e8 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Bharat, V. et al. Capture of dense core vesicles at synapses by JNK-dependent phosphorylation of synaptotagmin-4. Cell Rep. 21, 2118–2133 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Zhang, W. & Benson, D. L. Stages of synapse development defined by dependence on F-actin. J. Neurosci. 21, 5169–5181 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Chia, P. H., Patel, M. R. & Shen, K. NAB-1 instructs synapse assembly by linking adhesion molecules and F-actin to active zone proteins. Nat. Neurosci. 15, 234–242 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Chia, P. H., Chen, B., Li, P., Rosen, M. K. & Shen, K. Local F-actin network links synapse formation and axon branching. Cell 156, 208–220 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Rust, M. B. ADF/cofilin: a crucial regulator of synapse physiology and behavior. Cell. Mol. Life Sci. 72, 3521–3529 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Tedeschi, A. et al. ADF/cofilin-mediated actin turnover promotes axon regeneration in the adult CNS. Neuron 103, 1073–1085.e6 (2019). Rejuvenating actin dynamics at the growth cone — a major intracellular process enabling rapid axon growth during embryonic development — promotes regeneration of mature axons following CNS injury.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Pinto-Costa, R. et al. Profilin 1 delivery tunes cytoskeletal dynamics toward CNS axon regeneration. J. Clin. Invest. 130, 2024–2040 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Stern, S. et al. RhoA drives actin compaction to restrict axon regeneration and astrocyte reactivity after CNS injury. Neuron 109, 3436–3455.e9 (2021). The small GTPase RhoA has opposing roles in neurons and reactive astrocytes following CNS injury: neuronal RhoA prevents axon regeneration but astrocytic RhoA is beneficial for regenerating axons.

    Article  CAS  PubMed  Google Scholar 

  210. Shekhtmeyster, P. et al. Trans-segmental imaging in the spinal cord of behaving mice. Nat. Biotechnol. 41, 1729–1733 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Schafer, S. T. et al. An in vivo neuroimmune organoid model to study human microglia phenotypes. Cell 186, 2111–2126.e20 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Skinnider, M. A. et al. Single-cell and spatial atlases of spinal cord injury in the Tabulae Paralytica. Nature 631, 150–163 (2024).

    Article  CAS  PubMed  Google Scholar 

  213. Matson, K. J. et al. Single cell atlas of spinal cord injury in mice reveals a pro-regenerative signature in spinocerebellar neurons. Nat. Commun. 13, 5628 (2022). This paper generated an atlas using single-nucleus sequencing to profile how different cell types respond to spinal cord injury and showed that a specific subpopulation (spinocerebellar neurons) has a higher capacity to sprout and form new circuits in the injured spinal cord.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Squair, J. W. et al. Recovery of walking after paralysis by regenerating characterized neurons to their natural target region. Science 381, 1338–1345 (2023). This paper demonstrates the importance of neuronal identity in functional axon regeneration following CNS injury.

    Article  CAS  PubMed  Google Scholar 

  215. Yang, S.-G., Wang, X.-W., Qian, C. & Zhou, F.-Q. Reprogramming neurons for regeneration: the fountain of youth. Prog. Neurobiol. 214, 102284 (2022).

    Article  CAS  PubMed  Google Scholar 

  216. Lundberg, E. & Borner, G. H. Spatial proteomics: a powerful discovery tool for cell biology. Nat. Rev. Mol. Cell Biol. 20, 285–302 (2019).

    Article  CAS  PubMed  Google Scholar 

  217. Banker, G. The development of neuronal polarity: a retrospective view. J. Neurosci. 38, 1867–1873 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Hilton, B. J. & Bradke, F. Can injured adult CNS axons regenerate by recapitulating development? Development 144, 3417–3429 (2017).

    Article  CAS  PubMed  Google Scholar 

  219. Shen, Y. et al. PTPσ is a receptor for chondroitin sulfate proteoglycan, an inhibitor of neural regeneration. Science 326, 592–596 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Smith, G. M. & Gallo, G. The role of mitochondria in axon development and regeneration. Dev. Neurobiol. 78, 221–237 (2018).

    Article  CAS  PubMed  Google Scholar 

  221. Kapitein, L. C. & Hoogenraad, C. C. Which way to go? Cytoskeletal organization and polarized transport in neurons. Mol. Cell Neurosci. 46, 9–20 (2011).

    Article  CAS  PubMed  Google Scholar 

  222. Farias, G. G., Guardia, C. M., Britt, D. J., Guo, X. & Bonifacino, J. S. Sorting of dendritic and axonal vesicles at the pre-axonal exclusion zone. Cell Rep. 13, 1221–1232 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Huber, L. A. et al. Protein transport to the dendritic plasma membrane of cultured neurons is regulated by rab8p. J. Cell Biol. 123, 47–55 (1993).

    Article  CAS  PubMed  Google Scholar 

  224. Mignogna, M. L. & D’Adamo, P. Critical importance of RAB proteins for synaptic function. Small GTPases 9, 145–157 (2018).

    Article  CAS  PubMed  Google Scholar 

  225. Zhou, F.-Q. & Snider, W. D. Intracellular control of developmental and regenerative axon growth. Philos. Trans. R. Soc. B Biol. Sci. 361, 1575–1592 (2006).

    Article  CAS  Google Scholar 

  226. Park, K. K., Liu, K., Hu, Y., Kanter, J. L. & He, Z. PTEN/mTOR and axon regeneration. Exp. Neurol. 223, 45–50 (2010).

    Article  CAS  PubMed  Google Scholar 

  227. Gentile, J. E., Carrizales, M. G. & Koleske, A. J. Control of synapse structure and function by actin and its regulators. Cells 11, 603 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

B.J.H. is supported by the Natural Sciences and Engineering Research Council of Canada (RGPIN-2024-03986), the Canadian Foundation for Innovation, and the Michael Smith Foundation for Health Research BC. This work was supported by Deutsche Forschungsgesellschaft (DFG), the International Foundation for Research in Paraplegia (IRP) and Wings for Life (to F.B). F.B. is a member of the excellence cluster ImmunoSensation2, the SFBs 1089 and 1158, and is a recipient of the Roger De Spoelberch Prize. We also thank P. Scheiffele for discussions.

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B.J.H., J.W.F., J.M.G. and F.B. researched data for the article. B.J.H., J.W.F and F.B. wrote the article. All authors contributed substantially to discussion of the content and reviewed and/or edited the manuscript before submission.

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Correspondence to Brett J. Hilton, James W. Fawcett or Frank Bradke.

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Nature Reviews Neuroscience thanks Vibhu Sahni, who co-reviewed with Julia Kaiser; Binhai Zheng, who co-reviewed with Carmine Chavez-Martinez; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Active zone

The section of the presynaptic plasma membrane within which synaptic vesicle exocytosis takes place.

Autophagosome

A double-membraned vesicle that is formed during autophagy and engulfs and degrades intracellular material.

Axon initial segment

(AIS). The region of the axon close to the soma. The AIS is responsible for the generation of action potentials and demarcates the boundary between axonal and somatodendritic compartments of the neuron.

Cell adhesion molecules

Proteins located on the surface of the cell that mediate interactions between cells or between cells and the extracellular matrix.

Chromatin

The combination of DNA and histone proteins that together comprise chromosomes.

Cytoskeletal dynamics

The interactions between cytoskeletal filaments and accessory proteins that dictate cytoskeletal assembly, disassembly and function.

Differentiation

The process through which immature and less specialized cells acquire structural and functional specificity.

Endosomes

Membrane-bound vesicles that have a role in intracellular sorting in eukaryotic cells.

Enhancers

Sequences of DNA that are located in proximity to a gene and that can be bound by proteins to enhance the likelihood of that gene’s transcription.

Epigenetic mechanisms

Processes that regulate gene expression without changing the DNA sequence.

Extracellular matrix

The network of extracellular molecules that provide structural and biochemical support to cells.

Growth cone

A specialized and motile structure found at the distal tip of a growing neurite.

Local translation

Synthesis of proteins at a specialized site within the cell, such as the axon, dendrite, or synapse.

Microtubule

A polymer of tubulin that is a major part of the cytoskeleton.

Nucleosomes

Segments of DNA wound around histone proteins, constituting the fundamental organization of DNA packaging and resembling ‘beads on a string’.

Promoters

Sequences of DNA to which proteins can bind in order to initiate the transcription of RNA.

Regeneration-associated genes

(RAGs). A historical term in the axon regeneration field referring to genes with expression profiles that positively correlate with axon growth competence, such as those upregulated after peripheral nerve injury.

Retrograde injury signalling

The process by which the neuron signals from its injured axon back to its nucleus to orchestrate the cell body’s response to injury.

Transcytosis

A type of specialized transport in which molecules and/or cargo are taken into a vesicle, transported to a different area of the cell and then secreted.

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Hilton, B.J., Griffin, J.M., Fawcett, J.W. et al. Neuronal maturation and axon regeneration: unfixing circuitry to enable repair. Nat. Rev. Neurosci. 25, 649–667 (2024). https://doi.org/10.1038/s41583-024-00849-3

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  • DOI: https://doi.org/10.1038/s41583-024-00849-3

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