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Molecular Brain Feb 2021Axon regeneration in the central nervous system is inefficient. However, the neurons in the peripheral nervous system display robust regeneration after injury,...
Axon regeneration in the central nervous system is inefficient. However, the neurons in the peripheral nervous system display robust regeneration after injury, indicating that axonal regeneration is differentially controlled under various conditions. To identify those molecules regulating axon regeneration, comparative analysis from dorsal root ganglion neurons at embryonic or adult stages is utilized, which reveals that PDK1 is functions as a negative regulator of axon regeneration. PDK1 is downregulated in embryonic neurons after axotomy. In contrast, sciatic nerve axotomy upregulated PDK1 at protein levels from adult mice. The knockdown of PDK1 or the chemical inhibition of PDK1 promotes axon regeneration in vitro and in vivo. Here we present PDK1 as a new player to negatively regulate axon regeneration and as a potential target in the development of therapeutic applications.
Topics: 3-Phosphoinositide-Dependent Protein Kinases; Animals; Axons; Axotomy; Down-Regulation; Ganglia, Spinal; Indazoles; MAP Kinase Signaling System; Mice; Nerve Regeneration; Pyrimidines; Sciatic Nerve; TRPP Cation Channels; Up-Regulation
PubMed: 33579325
DOI: 10.1186/s13041-021-00748-z -
Open Biology Jun 2023The mechanism of axon growth and guidance is a core, unsolved problem in neuroscience and cell biology. For nearly three decades, our view of this process has largely...
The mechanism of axon growth and guidance is a core, unsolved problem in neuroscience and cell biology. For nearly three decades, our view of this process has largely been based on deterministic models of motility derived from studies of neurons cultured on rigid substrates. Here, we suggest a fundamentally different, inherently probabilistic model of axon growth, one that is grounded in the stochastic dynamics of actin networks. This perspective is motivated and supported by a synthesis of results from live imaging of a specific axon growing in its native tissue , together with single-molecule computational simulations of actin dynamics. In particular, we show how axon growth arises from a small spatial bias in the intrinsic fluctuations of the axonal actin cytoskeleton, one that produces net translocation of the axonal actin network by differentially modulating local probabilities of network expansion versus compaction. We discuss the relationship between this model and current views of axon growth and guidance mechanism and demonstrate how it offers explanations for various longstanding puzzles in this field. We further point out the implications of the probabilistic nature of actin dynamics for many other processes of cell morphology and motility.
Topics: Actins; Growth Cones; Axons; Neurons; Actin Cytoskeleton
PubMed: 37282493
DOI: 10.1098/rsob.220359 -
The Journal of Physiology Nov 2012The axon initial segment (AIS) that separates axonal and somato-dendritic compartments is a highly specialised neuronal structure enriched with voltage-gated Na(+)... (Review)
Review
The axon initial segment (AIS) that separates axonal and somato-dendritic compartments is a highly specialised neuronal structure enriched with voltage-gated Na(+) channels and functions as the site of spike initiation in neurons. The AIS was once thought to be uniform and static in structure, but has been found to be organised in a manner specific to the function of individual neurons and to exhibit plasticity with changes in synaptic inputs. Such structural specialisations are found in the avian auditory system. In the nucleus magnocellularis (NM), which is involved in a precise relay of timing information, the length of the AIS differs depending on sound frequency and increases with decreasing frequencies to accommodate frequency-specific variations in synaptic inputs. In the nucleus laminaris, which integrates the timing information from both NMs for sound localisation, the length and the location of the AIS vary depending on sound frequency: AISs are shorter and more remote for higher frequency. Furthermore, the AISs of NM neurons elongate to increase their excitability when synaptic inputs are removed by cochlea ablation, suggesting their contribution to the homeostatic control of neural activity. These structural tunings and plasticities of the AIS are thus indispensable for the function of the auditory circuits in both normal and pathological conditions.
Topics: Animals; Auditory Pathways; Axons; Basal Nucleus of Meynert; Neuronal Plasticity; Neurons
PubMed: 23027822
DOI: 10.1113/jphysiol.2012.237305 -
Current Topics in Medicinal Chemistry 2024An abundance of studies from different international groups have demonstrated tracers along linear pathways resembling meridians over the body surface of humans. All... (Review)
Review
An abundance of studies from different international groups have demonstrated tracers along linear pathways resembling meridians over the body surface of humans. All experiments of the studies have been conducted by injection of a radiotracer solution or tracer dyes in a volume of solution into acupuncture points (acupoints). The solution injected into acupoints produces much stronger mechanical stimuli than acupuncture, which causes axon reflex. Anatomical studies have demonstrated that acupoints/meridians exist higher number of small nerve fibers and blood vessels with rich nitric oxide (NO) and neuropeptides in the cutaneous tissues as structures for the biomolecules mediated axon reflexes. Recent advances have determined that NO and calcitonin generelated peptides play crucial roles in the comprehension of the axon reflex. The stimuli-evoked axon reflex and NOergic biomolecules/neuropeptides increase local blood flow with higher levels in acupoints/meridians, which move radioactive substances or tracer dyes in the skin and subcutaneous tissue under a linear path resembling acupoints and meridians, the important phenomena of meridians induced by the stimuli. The evidence and understanding of the biomolecular processes of the tracers along linear pathways resembling meridians have been summarized with an emphasis on recent developments of NO and neuropeptides mediating stimuli-evoked axon reflexes to increase local blood flow with higher levels in acupoints/meridians, which move radioactive substances or tracer dyes in the skin and subcutaneous tissue contributing to tracers along linear pathways resembling meridians in this mini-review.
Topics: Humans; Neuropeptides; Meridians; Axons; Nitric Oxide; Animals; Reflex
PubMed: 38243932
DOI: 10.2174/0115680266260220240108114337 -
The Journal of Neuroscience : the... Aug 2021Understanding the bioenergetics of axon extension and maintenance has wide ranging implications for neurodevelopment and disease states. Glycolysis is a pathway...
Understanding the bioenergetics of axon extension and maintenance has wide ranging implications for neurodevelopment and disease states. Glycolysis is a pathway consisting of 10 enzymes and separated into preparatory and payoff phases, the latter producing ATP. Using embryonic chicken sensory neurons, we report that glycolytic enzymes are found through the axon and the growth cone. Pharmacological inhibition of glycolysis in the presence of NGF impairs axon extension and growth cone dynamics within minutes without affecting axon maintenance. Experiments using microfluidic chambers show that the effect of inhibiting glycolysis on axon extension is local along distal axons and can be reversed by promoting mitochondrial respiration. Knockdown of GAPDH simplifies growth cone morphology and is rescued by shRNA-resistant GAPDH expression. Rescue of GAPDH using KillerRed fused to GAPDH followed by localized chromophore-assisted light inactivation of KillerRed-GAPDH in distal axons halts growth cone dynamics. Considering filament polymerization requires ATP, inhibition of glycolysis results in a paradoxical increase in axonal actin filament levels. The effect on actin filaments is because of enzymes before GAPDH, the first enzyme in the payoff phase. In the absence of NGF, inhibition of glycolysis along distal axons results in axon degeneration independent of cell death. These data indicate that the glycolytic pathway is operative in distal axons and contributes to the rate of axon extension and growth cone dynamics in the presence of NGF and that, in the absence of NGF, the axonal glycolytic pathway is required for axon maintenance. Elucidation of the sources of ATP required for axon extension and maintenance has implications for understanding the mechanism of neuronal development and diseases of the nervous system. While recent work has emphasized the importance of mitochondrial oxidative phosphorylation, the role of the glycolytic pathway in axon morphogenesis and maintenance remains minimally understood. The data reveal that the glycolytic pathway is required for normal sensory axon extension in the presence of NGF, while in the absence of NGF the glycolytic pathway is required for axon maintenance. The results have implications for the understanding of the bioenergetics of axon morphogenesis and plasticity and indicate that NGF has protective effects on sensory axon maintenance in hypoglycemic states.
Topics: Animals; Axon Guidance; Axons; Chick Embryo; Glycolysis; Growth Cones; Sensory Receptor Cells
PubMed: 34252036
DOI: 10.1523/JNEUROSCI.0321-21.2021 -
Bioarchitecture 2013The NAD-synthesizing enzyme NMNAT2 is critical for axon survival in primary culture and its depletion may contribute to axon degeneration in a variety of...
The NAD-synthesizing enzyme NMNAT2 is critical for axon survival in primary culture and its depletion may contribute to axon degeneration in a variety of neurodegenerative disorders. Here we discuss several recent reports from our laboratory that establish a critical role for NMNAT2 in axon growth in vivo in mice and shed light on the delivery and turnover of this survival factor in axons. In the absence of NMNAT2, axons fail to extend more than a short distance beyond the cell body during embryonic development, implying a requirement for NMNAT2 in axon maintenance even during development. Furthermore, we highlight findings regarding the bidirectional trafficking of NMNAT2 in axons on a vesicle population that undergoes fast axonal transport in primary culture neurites and in mouse sciatic nerve axons in vivo. Surprisingly, loss of vesicle association boosts the axon protective capacity of NMNAT2, an effect that is at least partially mediated by a longer protein half-life of cytosolic NMNAT2 variants. Analysis of wild-type and variant NMNAT2 in mouse sciatic nerves and Drosophila olfactory receptor neuron axons supports the existence of a similar mechanism in vivo, highlighting the potential for regulation of NMNAT2 stability and turnover as a mechanism to modulate axon degeneration in vivo.
Topics: Animals; Axons; Gene Deletion; Nerve Degeneration; Neurites; Nicotinamide-Nucleotide Adenylyltransferase; Subcellular Fractions; Wallerian Degeneration
PubMed: 24284888
DOI: 10.4161/bioa.27049 -
EMBO Reports Nov 2022Our understanding of the cell behaviours and cytoskeletal requirements of axon formation is largely derived from in vitro models but how these relate to axon formation...
Our understanding of the cell behaviours and cytoskeletal requirements of axon formation is largely derived from in vitro models but how these relate to axon formation in vivo is not clear. In vitro, neurons progress through a well-defined multineurite stage to form an axon and both actin and microtubules cooperate to drive the first steps in neurite and axon morphogenesis. However, these steps are not recapitulated in vivo, and it is not clear whether the underlying cell biological mechanisms may differ also. Here, we investigate the mechanisms that regulate axon formation in embryonic zebrafish spinal neurons in vivo. We find microtubule organising centres are located distant from the site of axon initiation, and microtubule plus-ends are not enriched in the axon during axon initiation. Focal F-actin accumulation precedes axon formation, and we find that nocodazole-treated neurons with no detectable microtubules are still able to form nascent axonal protrusions that are approximately 10-μm long, dilated and relatively long-lived. We suggest spinal axon formation in vivo is fundamentally different from axon formation in in vitro models.
Topics: Animals; Zebrafish; Microtubules; Axons; Neurons; Neurites; Actins
PubMed: 36194673
DOI: 10.15252/embr.202152493 -
Acta Pharmacologica Sinica Jan 2016Axon initial segment (AIS) is the proximal part of the axon, which is not covered with a myelin sheath and possesses a distinctive, specialized assembly of voltage-gated... (Review)
Review
Axon initial segment (AIS) is the proximal part of the axon, which is not covered with a myelin sheath and possesses a distinctive, specialized assembly of voltage-gated ion channels and associated proteins. AIS plays critical roles in synaptic integration and action potential generation in central neurons. Recent evidence shows that stroke causes rapid, irreversible calpain-mediated proteolysis of the AIS cytoskeleton of neurons surrounding the ischemic necrotic core. A better understanding of the molecular mechanisms underlying this "non-lethal" neuronal damage might provide new therapeutic strategies for improving stroke outcome. Here, we present a brief overview of the structure and function of the AIS. We then discuss possible mechanisms underlying stroke-induced AIS damage, including the roles of calpains and possible sources of Ca(2+) ions, which are necessary for the activation of calpains. Finally, we discuss the potential functional implications of the loss of the AIS cytoskeleton and ion channel clusters for neuronal excitability.
Topics: Animals; Axons; Cytoskeleton; Humans; Ion Channels; Neuronal Plasticity; Stroke
PubMed: 26687934
DOI: 10.1038/aps.2015.107 -
Current Biology : CB Aug 2019Synaptic vesicles are indispensable for neuronal communication in mature circuits. Synaptic vesicle biogenesis must be concurrent with axon navigation for...
Synaptic vesicles are indispensable for neuronal communication in mature circuits. Synaptic vesicle biogenesis must be concurrent with axon navigation for synaptogenesis, but whether synaptic vesicles are functionally employed in circuit formation before synaptogenesis is poorly understood. Here, we use time-lapse imaging and transgenesis in zebrafish to visualize the role of synaptic-like vesicles in navigation of dorsal root ganglia pioneer axons. We identify that synaptic-like vesicles accumulate in the central growth cone as the pioneer axon breaches the spinal boundary at the dorsal root entry zone. Inhibition of vesicle release with cell-specific tetanus toxin expression results in pioneer axon pathfinding defects and altered spinal entry. We further show that the matrix metalloproteinase (MMP) mmp14a is required in pioneer axons to navigate across the boundary of the spinal cord and, with super-resolution microscopy, is positioned with synaptic vesicles at the boundary. Manipulations of concurrent actin reorganization reveal that actin remodeling drives vesicle release and subsequent MMP activity. Together, these data point to an indispensable role for synaptic-like vesicles at specific points in axon navigation as regulators of growth cone microenvironment.
Topics: Animals; Axons; Ganglia, Spinal; Growth Cones; Synaptic Vesicles; Zebrafish
PubMed: 31378609
DOI: 10.1016/j.cub.2019.06.078 -
Developmental Dynamics : An Official... Jan 2023Sensory neurons of the head are the ones that transmit the information about the external world to our brain for its processing. Axons from cranial sensory neurons sense... (Review)
Review
Sensory neurons of the head are the ones that transmit the information about the external world to our brain for its processing. Axons from cranial sensory neurons sense different chemoattractant and chemorepulsive molecules during the journey and in the target tissue to establish the precise innervation with brain neurons and/or receptor cells. Here, we aim to unify and summarize the available information regarding molecular mechanisms guiding the different afferent sensory axons of the head. By putting the information together, we find the use of similar guidance cues in different sensory systems but in distinct combinations. In vertebrates, the number of genes in each family of guidance cues has suffered a great expansion in the genome, providing redundancy, and robustness. We also discuss recently published data involving the role of glia and mechanical forces in shaping the axon paths. Finally, we highlight the remaining questions to be addressed in the field.
Topics: Animals; Axon Guidance; Axons; Sensory Receptor Cells; Neuroglia; Sense Organs
PubMed: 35972036
DOI: 10.1002/dvdy.523