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Current Opinion in Neurobiology Aug 2018The axon initial segment (AIS) is a unique domain of the proximal axon serving critical electrical and structural roles including the initiation of action potentials and... (Review)
Review
The axon initial segment (AIS) is a unique domain of the proximal axon serving critical electrical and structural roles including the initiation of action potentials and maintenance of cellular polarity. Recent experimental and theoretical advances demonstrate that the anatomical site for initiation is remarkably diverse. The AIS location varies not only axially, along the axon, but axons also emerge variably from either the soma or proximal dendrites. Here, we review the evidence that the diversity of AIS and axon location has a substantial impact on the electrical properties and speculate that the anatomical heterogeneity of axon locations expands synaptic integration within cell types and improves information processing in neural circuits.
Topics: Animals; Axon Initial Segment; Axons; Cell Polarity; Membrane Potentials; Neurons; Synapses
PubMed: 29533849
DOI: 10.1016/j.conb.2018.02.016 -
Cell and Tissue Research Jul 2012After central nervous system (CNS) trauma, axons have a low capacity for regeneration. Regeneration failure is associated with a muted regenerative response of the... (Review)
Review
After central nervous system (CNS) trauma, axons have a low capacity for regeneration. Regeneration failure is associated with a muted regenerative response of the neuron itself, combined with a growth-inhibitory and cytotoxic post-injury environment. After spinal cord injury (SCI), resident and infiltrating immune cells (especially microglia/macrophages) contribute significantly to the growth-refractory milieu near the lesion. By targeting both the regenerative potential of the axon and the cytotoxic phenotype of microglia/macrophages, we may be able to improve CNS repair after SCI. In this review, we discuss molecules shown to impact CNS repair by affecting both immune cells and neurons. Specifically, we provide examples of pattern recognition receptors, integrins, cytokines/chemokines, nuclear receptors and galectins that could improve CNS repair. In many cases, signaling by these molecules is complex and may have contradictory effects on recovery depending on the cell types involved or the model studied. Despite this caveat, deciphering convergent signaling pathways on immune cells (which affect axon growth indirectly) and neurons (direct effects on axon growth) could improve repair and recovery after SCI. Future studies must continue to consider how regenerative therapies targeting neurons impact other cells in the pathological CNS. By identifying molecules that simultaneously improve axon regenerative capacity and drive the protective, growth-promoting phenotype of immune cells, we may discover SCI therapies that act synergistically to improve CNS repair and functional recovery.
Topics: Animals; Axons; Central Nervous System; Humans; Nerve Regeneration; Receptors, Pattern Recognition; Signal Transduction
PubMed: 22592625
DOI: 10.1007/s00441-012-1425-5 -
The Journal of Experimental Biology Feb 2015Polarized distribution of signaling molecules to axons and dendrites facilitates directional information flow in complex vertebrate nervous systems. The topic we address... (Review)
Review
Polarized distribution of signaling molecules to axons and dendrites facilitates directional information flow in complex vertebrate nervous systems. The topic we address here is when the key aspects of neuronal polarity evolved. All neurons have a central cell body with thin processes that extend from it to cover long distances, and they also all rely on voltage-gated ion channels to propagate signals along their length. The most familiar neurons, those in vertebrates, have additional cellular features that allow them to send directional signals efficiently. In these neurons, dendrites typically receive signals and axons send signals. It has been suggested that many of the distinct features of axons and dendrites, including the axon initial segment, are found only in vertebrates. However, it is now becoming clear that two key cytoskeletal features that underlie polarized sorting, a specialized region at the base of the axon and polarized microtubules, are found in invertebrate neurons as well. It thus seems likely that all bilaterians generate axons and dendrites in the same way. As a next step, it will be extremely interesting to determine whether the nerve nets of cnidarians and ctenophores also contain polarized neurons with true axons and dendrites, or whether polarity evolved in concert with the more centralized nervous systems found in bilaterians.
Topics: Animals; Axons; Biological Evolution; Cytoskeleton; Dendrites; Invertebrates; Microtubules; Neurons
PubMed: 25696820
DOI: 10.1242/jeb.112359 -
Cell Reports Feb 2024Inflammation is closely associated with many neurodegenerative disorders. Yet, whether inflammation causes, exacerbates, or responds to neurodegeneration has been...
Inflammation is closely associated with many neurodegenerative disorders. Yet, whether inflammation causes, exacerbates, or responds to neurodegeneration has been challenging to define because the two processes are so closely linked. Here, we disentangle inflammation from the axon damage it causes by individually blocking cytotoxic T cell function and axon degeneration. We model inflammatory damage in mouse skin, a barrier tissue that, despite frequent inflammation, must maintain proper functioning of a dense array of axon terminals. We show that sympathetic axons modulate skin inflammation through release of norepinephrine, which suppresses activation of γδ T cells via the β2 adrenergic receptor. Strong inflammatory stimulation-modeled by application of the Toll-like receptor 7 agonist imiquimod-causes progressive γδ T cell-mediated, Sarm1-dependent loss of these immunosuppressive sympathetic axons. This removes a physiological brake on T cells, initiating a positive feedback loop of enhanced inflammation and further axon damage.
Topics: Animals; Mice; Feedback; Inflammation; Axons; Dermatitis; Presynaptic Terminals
PubMed: 38310514
DOI: 10.1016/j.celrep.2024.113721 -
International Journal of Molecular... Aug 2021During neuronal development and regeneration axons extend a cytoskeletal-rich structure known as the growth cone, which detects and integrates signals to reach its final... (Review)
Review
During neuronal development and regeneration axons extend a cytoskeletal-rich structure known as the growth cone, which detects and integrates signals to reach its final destination. The guidance cues "signals" bind their receptors, activating signaling cascades that result in the regulation of the growth cone cytoskeleton, defining growth cone advance, pausing, turning, or collapse. Even though much is known about guidance cues and their isolated mechanisms during nervous system development, there is still a gap in the understanding of the crosstalk between them, and about what happens after nervous system injuries. After neuronal injuries in mammals, only axons in the peripheral nervous system are able to regenerate, while the ones from the central nervous system fail to do so. Therefore, untangling the guidance cues mechanisms, as well as their behavior and characterization after axotomy and regeneration, are of special interest for understanding and treating neuronal injuries. In this review, we present findings on growth cone guidance and canonical guidance cues mechanisms, followed by a description and comparison of growth cone pathfinding mechanisms after axotomy, in regenerative and non-regenerative animal models.
Topics: Animals; Axon Guidance; Axons; Axotomy; Growth Cones; Humans; Nerve Regeneration; Signal Transduction
PubMed: 34361110
DOI: 10.3390/ijms22158344 -
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 -
Current Opinion in Neurobiology Feb 2011Axon regeneration has long been studied in vertebrate model organisms and neuronal cultures. Recent development of axon regeneration paradigms in genetic model... (Review)
Review
Axon regeneration has long been studied in vertebrate model organisms and neuronal cultures. Recent development of axon regeneration paradigms in genetic model organisms, such as Caenorhabditis elegans, Drosophila and zebrafish, has opened an exciting field for in vivo functional dissection of regeneration pathways. Studies in these organisms have discovered essential genes and pathways for axon regrowth. The conservation of these genes crossing animal phyla suggests mechanistic relevance to higher organisms. The power of genetic approaches in these organisms makes large-scale genetic and pharmacological screens feasible and can greatly accelerate the mechanistic understanding of axon regeneration.
Topics: Animals; Axons; Humans; Nerve Regeneration
PubMed: 20832288
DOI: 10.1016/j.conb.2010.08.010 -
Current Opinion in Neurobiology Dec 2013A remarkable feature of nervous system development is the ability of axons emerging from newly formed neurons to traverse, by cellular scale, colossal distances to... (Review)
Review
A remarkable feature of nervous system development is the ability of axons emerging from newly formed neurons to traverse, by cellular scale, colossal distances to appropriate targets. The earliest axons achieve this in an essentially axon-free environment, but the vast majority of axons eventually grow along a scaffold of nerve tracts created by earlier extending axons. Signal exchange between sequentially or simultaneously extending axons may well represent the predominant mode of axonal navigation, but proportionally few efforts have so far been directed at deciphering the underlying mechanisms. This review intends to provide a conceptual update on the cellular and molecular principles driving axon-axon interactions, with emphasis on those contributing to the fidelity of axonal navigation, sorting and connectivity during nerve and circuit assembly.
Topics: Animals; Axons; Cell Communication; Humans; Neurogenesis; Signal Transduction
PubMed: 23973157
DOI: 10.1016/j.conb.2013.08.004 -
Current Opinion in Neurobiology Dec 2018Understanding how neurons form, extend, and navigate their finger-like axonal and dendritic processes is crucial for developing therapeutics for the diseased and damaged... (Review)
Review
Understanding how neurons form, extend, and navigate their finger-like axonal and dendritic processes is crucial for developing therapeutics for the diseased and damaged brain. Although less well appreciated, many other types of cells also send out similar finger-like projections. Indeed, unlike neuronal specific phenomena such as synapse formation or synaptic transmission, an important issue for thought is that this critical long-standing question of how a cellular process like an axon or dendrite forms and extends is not primarily a neuroscience problem but a cell biological problem. In that case, the use of simple cellular processes - such as the bristle cell process of Drosophila - can aid in the fight to answer these critical questions. Specifically, determining how a model cellular process is generated can provide a framework for manipulations of all types of membranous process-containing cells, including different types of neurons.
Topics: Animals; Axons; Cell Biology; Models, Biological; Neurosciences
PubMed: 30248549
DOI: 10.1016/j.conb.2018.08.004 -
Neuroscience Letters Apr 2019Neurons are long-lived and highly polarized cells that depend on autophagy to maintain cellular homeostasis. The robust, constitutive biogenesis of autophagosomes in the... (Review)
Review
Neurons are long-lived and highly polarized cells that depend on autophagy to maintain cellular homeostasis. The robust, constitutive biogenesis of autophagosomes in the distal axon occurs via a conserved pathway that is required to maintain functional synapses and prevent axon degeneration. Autophagosomes are formed de novo at the axon terminal in a stepwise assembly process, engulfing mitochondrial fragments, aggregated proteins, and bulk cytosol in what appears to be a nonselective uptake mechanism. Following formation, autophagosomes fuse with late endosomes/lysosomes and then are rapidly and efficiently transported along the axon toward the soma, driven by the microtubule motor cytoplasmic dynein. Motile autophagosomes mature to autolysosomes in transit by fusing with additional late endosomes/lysosomes, arriving at the soma as fully competent degradative organelles. Misregulation of neuronal autophagy leads to axonal degeneration and synaptic destabilization, and has been implicated in neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and ALS.
Topics: Animals; Autophagosomes; Autophagy; Axons; Central Nervous System; Endosomes; Homeostasis; Humans; Lysosomes; Neurodegenerative Diseases; Neurons; Protein Transport
PubMed: 29548988
DOI: 10.1016/j.neulet.2018.03.025