An active vesicle priming machinery suppresses axon regeneration upon adult CNS injury

Hilton, Brett J.; Husch, Andreas; Schaffran, Barbara; Lin, Tien-chen; Burnside, Emily R.; Dupraz, Sebastián; Schelski, Max; Kim, Ji-Soo; Müller, Johannes Alexander; Schoch, Susanne; Imig, Cordelia; Brose, Nils; Bradke, Frank

doi:10.1016/j.neuron.2021.10.007

Cited by 55 publications

(31 citation statements)

References 127 publications

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“…Therefore, our study suggested that Ezh2 upregulation might rejuvenate mature neurons at the transcriptomic level to empower them with stronger axon regeneration ability. In support of this, several previous studies also demonstrated that suppressed transcription of synaptic function-related genes positively correlated with enhanced axon regeneration ability (Hilton et al ., 2022; Norsworthy et al, 2017; Sekine et al, 2018; Wang et al, 2018b). On the other hand, Ezh2 overexpression also resulted in upregulation of many factors known to enhance axon regeneration, some of which are highly expressed in young developing neurons (Costales and Kolevzon, 2016; Penzo-Mendez, 2010; Zaytseva et al, 2020).…”

Section: Discussionsupporting

confidence: 70%

“…A previous study in larval sea lampreys showed that GABA promoted survival and axon regeneration of descending neurons after a complete spinal cord injury through GABA B receptors (Romaus-Sanjurjo et al, 2018). Two recent studies showed that activating GABA B receptors could promote axon regeneration in the mouse dorsal column and cortical spinal tract after spinal cord injury (Hilton et al, 2022; Li et al, 2020). We also investigated the role of Slc6a13 in regenerative axon growth of DRG neurons in vitro .…”

Section: Resultsmentioning

confidence: 99%

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Histone methyltransferase Ezh2 coordinates mammalian axon regeneration via epigenetic regulation of key regenerative pathways

Wang

Yang

et al. 2022

Preprint

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SummaryCurrent clinical treatment for neurodegenerative diseases and neural injuries falls short of success, and one primary reason is that neurons in the mammalian central nervous system (CNS) lose their regeneration ability as they mature. Previous studies indicated that the regeneration ability of neurons is governed by complex signaling networks involving many genes. Therefore, here we investigated the roles of Ezh2, a histone methyltransferase, in regulation of mammalian axon regeneration at the epigenetic level. We found that Ezh2 level was gradually downregulated in the mouse nervous system during maturation but significantly upregulated in mature sensory neurons during spontaneous axon regeneration in the peripheral nerve system (PNS), suggesting its role in supporting axon regeneration. Indeed, Ezh2 loss-of-function in sensory neurons impaired PNS axon regeneration in vitro and in vivo. In contrast, overexpression of Ezh2 in retinal ganglion cells in the CNS induced optic nerve regeneration after optic nerve injury in both methyltransferase-dependent and -independent manners. Mechanistic exploration with multiomics sequencing, together with functional analyses, revealed that Ezh2 supported axon regeneration by systematically silencing the transcription of genes regulating synaptic function and axon regeneration inhibitory signaling, while broadly activating factors promoting axon regeneration. Our study not only reveals that Ezh2 coordinates axon regeneration via epigenetically regulating multiple key regenerative pathways, but also suggests that modulating chromatin accessibility is a promising strategy to promote CNS axon regeneration.

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Section: Discussionsupporting

confidence: 70%

Section: Resultsmentioning

confidence: 99%

Histone methyltransferase Ezh2 coordinates mammalian axon regeneration via epigenetic regulation of key regenerative pathways

Wang

Yang

et al. 2022

Preprint

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“…Not only the whole toxins, but also their isolated catalytic domains that are genetically expressed, transfected, or microinjected within target cells have been widely used to study the role of specific SNARE proteins in membrane fusion events, in neurons, in other cell types, and even in animal hosts naturally unsusceptible to their uptake [85][86][87][88][89]. Their use associated with modern biotechnologies still represents a reliable, efficient, and definitely convenient method to block neuroexocytosis in several biological systems [90,91]. Among them, TeNT and BoNT/B and their derivatives, which cleave the identical peptide bond in VAMP-1/2/3, are widely used.…”

Section: Discussionmentioning

confidence: 99%

Detection of VAMP Proteolysis by Tetanus and Botulinum Neurotoxin Type B In Vivo with a Cleavage-Specific Antibody

Šoštarić

Matak

et al. 2022

IJMS

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Tetanus and Botulinum type B neurotoxins are bacterial metalloproteases that specifically cleave the vesicle-associated membrane protein VAMP at an identical peptide bond, resulting in inhibition of neuroexocytosis. The minute amounts of these neurotoxins commonly used in experimental animals are not detectable, nor is detection of their VAMP substrate sensitive enough. The immune detection of the cleaved substrate is much more sensitive, as we have previously shown for botulinum neurotoxin type A. Here, we describe the production in rabbit of a polyclonal antibody raised versus a peptide encompassing the 13 residues C-terminal with respect to the neurotoxin cleavage site. The antibody was affinity purified and found to recognize, with high specificity and selectivity, the novel N-terminus of VAMP that becomes exposed after cleavage by tetanus toxin and botulinum toxin type B. This antibody recognizes the neoepitope not only in native and denatured VAMP but also in cultured neurons and in neurons in vivo in neurotoxin-treated mice or rats, suggesting the great potential of this novel tool to elucidate tetanus and botulinum B toxin activity in vivo.

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“…One potential reason could be the apparent incompatibility seen elsewhere in the regenerating nervous system between axon growth and presynaptic maturation. After spinal cord injury in mice, several molecular components of presynaptic release machinery can act as a brake on re-growth in primary sensory axons (Hilton et al, 2021), suggesting that in order to get re-growing axons to their targets, full presynaptic function must be suppressed until the point of synaptic contact. Indeed, genes encoding presynaptic proteins are some of the last to be expressed in OSN development, at least under constitutive conditions (Marcucci et al, 2009; McClintock et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…Here even the most successful anatomical regeneration is usually accompanied by incomplete functional synaptic or behavioural recovery, suggestive of a disconnect between experimentally-induced axon regrowth and re-connectivity (Anderson et al, 2018; Ceto et al, 2020; Cheah et al, 2016; De Virgiliis et al, 2020; Fawcett, 2020; Lim et al, 2016; Lu et al, 2012; Wang et al, 2015). Indeed, it was recently shown that certain components of presynaptic release machinery act as a brake on axon regrowth after mammalian spinal cord injury, meaning that molecular mechanisms for promoting growth and those responsible for subsequent functional integration might be diametrically opposed (Hilton et al, 2021). But when even persuading re-growing mammalian central axons to reach their targets is already extremely difficult, how can we determine the additional manipulations required to promote their subsequent re-connectivity?…”

Section: Introductionmentioning

confidence: 99%

Rapid presynaptic maturation in naturally regenerating axons

Browne

Crespo

Grubb

2022

Preprint

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Successful neuronal regeneration requires the re-establishment of synaptic connectivity. Crucial to this process is the reconstitution of presynaptic machinery responsible for controlling neurotransmitter release. In the mammalian adult CNS post-injury regeneration is usually only possible after extensive experimental intervention, and it is unknown how presynaptic function is re-established, let alone how it might be optimised to promote functional recovery. Here we addressed these questions by studying presynaptic maturation during a regenerative process that occurs entirely naturally. After toxin-induced injury, olfactory sensory neurons in the adult mouse olfactory epithelium can regenerate fully, sending axons to the brain to re-establish synaptic contact with postsynaptic partners in the olfactory bulb. Using electrophysiological recordings in acute slices, we found that after initial re-contact, functional connectivity in this system was rapidly established. Moreover, re-connecting presynaptic terminals had almost mature functional properties, including high release probability and a strong capacity for presynaptic inhibition. Release probability then matured quickly, rendering re-established terminals functionally indistinguishable from controls just one week after initial contact. These data show that successful synaptic regeneration in the adult mammalian brain is not quite a ‘plug-and-play’ process; instead, almost-mature presynaptic terminals undergo a rapid phase of functional maturation to re-integrate into established target networks.

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An active vesicle priming machinery suppresses axon regeneration upon adult CNS injury

Cited by 55 publications

References 127 publications

Histone methyltransferase Ezh2 coordinates mammalian axon regeneration via epigenetic regulation of key regenerative pathways

Histone methyltransferase Ezh2 coordinates mammalian axon regeneration via epigenetic regulation of key regenerative pathways

Detection of VAMP Proteolysis by Tetanus and Botulinum Neurotoxin Type B In Vivo with a Cleavage-Specific Antibody

Rapid presynaptic maturation in naturally regenerating axons

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