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Cited by 9Nerve injury and regenerationCancer Treatment and PharmacologyMicrotubule and mitosis dynamics

In situ structural mechanism of epothilone-B-induced CNS axon regeneration

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Bodakuntla, Satish, Taira, Kenichiro, Yamada, Yurika, Alvarez-Brecht, Pelayo, Cada, A. King, Basnet, Nirakar, Zhang, Rui, Martinez-Sanchez, Antonio +2 more·2025·Nature
DOI 10.1038/s41586-025-09654-zPMC PMC12795760
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Abstract

Axons in the adult central nervous system (CNS) do not regenerate following injury, in contrast to neurons in the peripheral nervous system and neuronal growth during embryonic development. The molecular mechanisms that prevent regeneration of neurons in the CNS remain largely unknown 1,2 . Here, to address the intracellular response to injury, we developed an in situ cryo-electron tomography and cryo-electron microscopy platform to mimic axonal damage and present the structural mechanism underlying thalamic axon regeneration induced by the drug epothilone B. We observed that stabilized microtubules extend beyond the injury site, generating membrane tension and driving membrane expansion. Cryo-electron microscopy reveals the in situ structure of microtubules at 3.19 Å resolution, which engage epothilone B within the microtubule lattice at the regenerating front. During repair, tubulin clusters are delivered and incorporated into polymerizing microtubules at the regenerating site. These microtubule shoots serve as scaffolds for various types of vesicles and endoplasmic reticulum, facilitating the supply of materials necessary for axon repair until membrane tension normalizes. We demonstrate the unexpected ability of neuronal cells to adjust to strain induced by epothilone B, which creates homeostatic imbalances and activates axons to regeneration mode.

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  • Thalamus neural explants produced long neurites extending from brain tissue, allowing unambiguous assignment to axonal origins at this developmental stage.

    “We used thalamus neural explants, which produced long neurites extending from brain tissue, allowing unambiguous assignment to axonal origins at this developmental stage25,33,34.”

    From Ghost Neuron preparation unlocks high-resolution structural mapping of intracellular architecture in axons (2026) · cites this paper as [34]

    The Fig. 1 caption in “Cryo-EM platform for axon injury model” says embryonic thalamus explants extended axons from the tissue and describes their neurite extensions as axon-dominant. The Methods confirm that the explants came from E15.5 embryos. The source does not establish that every long neurite could be assigned unambiguously to an axonal origin; “axon-dominant” is a narrower claim. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Similar expanded lattice spacing was observed in a previous reconstruction of Epothilone B-stabilized microtubules at 3.19 Å resolution in regenerating axons, where membrane rupture also occurred during vitrification due to expanded membranes at regeneration sites, indicating membrane disruption itself does not distort lattice geometry.

    “Similar expanded lattice spacing was observed in our previous reconstruction of Epothilone B-stabilized microtubules at 3.19 Å resolution in regenerating axons34, where membrane rupture also occurred during vitrification due to expanded membranes at regeneration sites, indicating that membrane disruption itself does not distort lattice geometry.”

    From Ghost Neuron preparation unlocks high-resolution structural mapping of intracellular architecture in axons (2026) · cites this paper as [34]

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Authors
Bodakuntla, S., Taira, K., Yamada, Y., Alvarez-Brecht, P., Cada, A. K., Basnet, N., Zhang, R., Martinez-Sanchez, A., Biertümpfel, C., & Mizuno, N.
Affiliations
  • National Institutes of Health (US)
  • Washington University in St. Louis (US)
Corresponding author
Mizuno, Naoko
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2025-11-12
Volume
648
Issue
8093
Pages
477-487
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-025-09654-z
PMC
PMC12795760
OpenAlex
W4416146857
Cited by
9
References
1
Citations by year
2026: 8 · 2025: 1
FWCI
3.23
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion, cc-by)
  • Microscopy and Microanalysis (publishedVersion)
  • PubMed (publishedVersion)
  • Hispana (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by)
  • Research Explorer (The University of Manchester) (submittedVersion)
Funders
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (ZIAHL006264)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
  • Health Sciences › Medicine › Oncology › Cancer Treatment and Pharmacology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
Keywords
epothilone B, axon regeneration, central nervous system injury, microtubule stabilization, microtubule lattice, membrane tension, membrane expansion, axonal transport, endoplasmic reticulum, cryo-electron tomography, cryo-electron microscopy
MeSH terms
Animals, Axons, Cell Membrane, Endoplasmic Reticulum, Female, Homeostasis, Microtubules, Nerve Regeneration, Tubulin, Cryoelectron Microscopy, Epothilones, Mice, Rats, Electron Microscope Tomography

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