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Physiological Reviews Apr 2011Axons are generally considered as reliable transmission cables in which stable propagation occurs once an action potential is generated. Axon dysfunction occupies a... (Review)
Review
Axons are generally considered as reliable transmission cables in which stable propagation occurs once an action potential is generated. Axon dysfunction occupies a central position in many inherited and acquired neurological disorders that affect both peripheral and central neurons. Recent findings suggest that the functional and computational repertoire of the axon is much richer than traditionally thought. Beyond classical axonal propagation, intrinsic voltage-gated ionic currents together with the geometrical properties of the axon determine several complex operations that not only control signal processing in brain circuits but also neuronal timing and synaptic efficacy. Recent evidence for the implication of these forms of axonal computation in the short-term dynamics of neuronal communication is discussed. Finally, we review how neuronal activity regulates both axon morphology and axonal function on a long-term time scale during development and adulthood.
Topics: Action Potentials; Animals; Axons; Cell Proliferation; Channelopathies; Electrophysiological Phenomena; Humans; Ion Channels; Neuronal Plasticity; Signal Transduction; Synaptic Transmission
PubMed: 21527732
DOI: 10.1152/physrev.00048.2009 -
Seminars in Cell & Developmental Biology May 2023The axon is a sophisticated macromolecular machine composed of interrelated parts that transmit signals like spur gears transfer motion between parallel shafts. The... (Review)
Review
The axon is a sophisticated macromolecular machine composed of interrelated parts that transmit signals like spur gears transfer motion between parallel shafts. The growth cone is a fine sensor that integrates mechanical and chemical cues and transduces these signals through the generation of a traction force that pushes the tip and pulls the axon shaft forward. The axon shaft, in turn, senses this pulling force and transduces this signal in an orchestrated response, coordinating cytoskeleton remodeling and intercalated mass addition to sustain and support the advancing of the tip. Extensive research suggests that the direct application of active force is per se a powerful inducer of axon growth, potentially bypassing the contribution of the growth cone. This review provides a critical perspective on current knowledge of how the force is a messenger of axon growth and its mode of action for controlling navigation, including aspects that remain unclear. It also focuses on novel approaches and tools designed to mechanically manipulate axons, and discusses their implications in terms of potential novel therapies for re-wiring the nervous system.
Topics: Axons; Growth Cones; Actins; Neuronal Outgrowth
PubMed: 35817654
DOI: 10.1016/j.semcdb.2022.07.004 -
Current Opinion in Neurobiology Aug 2016Axon degeneration is an essential part of development, plasticity, and injury response and has been primarily studied in mammalian models in three contexts: 1)... (Review)
Review
Axon degeneration is an essential part of development, plasticity, and injury response and has been primarily studied in mammalian models in three contexts: 1) Axotomy-induced Wallerian degeneration, 2) Apoptosis-induced axon degeneration (axon apoptosis), and 3) Axon pruning. These three contexts dictate engagement of distinct pathways for axon degeneration. Recent advances have identified the importance of SARM1, NMNATs, NAD+ depletion, and MAPK signaling in axotomy-induced Wallerian degeneration. Interestingly, apoptosis-induced axon degeneration and axon pruning have many shared mechanisms both in signaling (e.g. DLK, JNKs, GSK3α/β) and execution (e.g. Puma, Bax, caspase-9, caspase-3). However, the specific mechanisms by which caspases are activated during apoptosis versus pruning appear distinct, with apoptosis requiring Apaf-1 but not caspase-6 while pruning requires caspase-6 but not Apaf-1.
Topics: Animals; Apoptosis; Axons; Caspases; Wallerian Degeneration
PubMed: 27197022
DOI: 10.1016/j.conb.2016.05.002 -
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 -
Neuroscience Jan 2023Investigating axonal behaviors while neurons are connecting with each other has been a challenge since the early studies on nervous system development. While... (Review)
Review
Investigating axonal behaviors while neurons are connecting with each other has been a challenge since the early studies on nervous system development. While molecule-driven axon pathfinding has been theorized by observing neurons at different developmental stages in vivo, direct observation and measurements of axon guidance behaviors required the invention of in vitro systems enabling to test the impact of molecules or cellular extracts on axons growing in vitro. With time, the development of novel in vivo approaches has confirmed the mechanisms highlighted in culture and has led in vitro systems to be adapted for cellular processes that are still inaccessible in intact organisms. We here review the evolution of these in vitro assays, which started with crucial contributions from the Bonhoeffer lab.
Topics: Axon Guidance; Axons; Neurons
PubMed: 36096337
DOI: 10.1016/j.neuroscience.2022.09.006 -
Molecular and Cellular Neurosciences Sep 2018Axon regeneration is a fundamental and conserved process that allows the nervous system to repair circuits after trauma. Due to its conserved genome, transparent body,... (Review)
Review
Axon regeneration is a fundamental and conserved process that allows the nervous system to repair circuits after trauma. Due to its conserved genome, transparent body, and relatively simple neuroanatomy, C. elegans has become a powerful model organism for studying the cellular and molecular mechanisms underlying axon regeneration. Various studies from different model organisms have found microtubule dynamics to be pivotal to axon regrowth. In this review, we will discuss the latest findings on how microtubule dynamics are regulated during axon regeneration in C. elegans. Understanding the mechanisms of axon regeneration will aid in the development of more effective therapeutic strategies for treatments of diseases involving disconnection of axons, such as spinal cord injury and stroke.
Topics: Animals; Axons; Caenorhabditis elegans; Microtubules; Nerve Regeneration
PubMed: 29551667
DOI: 10.1016/j.mcn.2018.03.007 -
Developmental Biology Sep 2022Neurons are highly polarized cells with extensive axonal and dendritic projections that send and receive signals over long distances. Neuronal polarity requires sorting... (Review)
Review
Neurons are highly polarized cells with extensive axonal and dendritic projections that send and receive signals over long distances. Neuronal polarity requires sorting and maintaining a unique set of proteins to the neuron's distinct axonal and somatodendritic domains. The axon initial segment (AIS) is a specialized subcellular region located between these two domains and is critical for neuronal polarity. The AIS has a complex and elaborately organized molecular structure that enables its functions in neuronal polarity. Disruption of the AIS is associated with neurodevelopmental and neuropsychiatric disease pathologies, thus highlighting the importance of the AIS in neuronal physiology. This review discusses recent progress toward understanding the molecular architecture of the AIS and its importance in neuronal polarity through regulating protein diffusion and vesicular trafficking.
Topics: Axon Initial Segment; Axons; Cell Polarity; Neurons; Protein Transport
PubMed: 35640681
DOI: 10.1016/j.ydbio.2022.05.016 -
Experimental Neurology Jan 2017Maintaining neuronal connectivity in the face of injury and disease is a major challenge for the nervous system. The great length of axons makes them particularly... (Review)
Review
Maintaining neuronal connectivity in the face of injury and disease is a major challenge for the nervous system. The great length of axons makes them particularly vulnerable to insult with dire consequences for neuronal function. In the peripheral nervous system there is a program of axonal regeneration that can reestablish connectivity. In the mammalian central nervous system, however, injured axons have little or no capacity to regenerate. The molecular mechanisms that promote axon regeneration have begun to be identified and many of the implicated pathways are evolutionarily conserved. Here we discuss Drosophila models of axonal regrowth, describe insights derived from these studies, and highlight future directions in the use of the fly for dissecting the mechanisms of axonal regeneration.
Topics: Animals; Animals, Genetically Modified; Axons; Disease Models, Animal; Drosophila; Drosophila Proteins; Mutation; Nerve Degeneration; Nerve Regeneration
PubMed: 26996133
DOI: 10.1016/j.expneurol.2016.03.014 -
Seminars in Cell & Developmental Biology May 2023Axon growth enables the rapid wiring of the central nervous system. Understanding this process is a prerequisite to retriggering it under pathological conditions, such... (Review)
Review
Axon growth enables the rapid wiring of the central nervous system. Understanding this process is a prerequisite to retriggering it under pathological conditions, such as a spinal cord injury, to elicit axon regeneration. The last decades saw progress in understanding the mechanisms underlying axon growth. Most of these studies employed cultured neurons grown on flat surfaces. Only recently studies on axon growth were performed in 3D. In these studies, physiological environments exposed more complex and dynamic aspects of axon development. Here, we describe current views on axon growth and highlight gaps in our knowledge. We discuss how axons interact with the extracellular matrix during development and the role of the growth cone and its cytoskeleton within. Finally, we propose that the time is ripe to study axon growth in a more physiological setting. This will help us uncover the physiologically relevant mechanisms underlying axon growth, and how they can be reactivated to induce axon regeneration.
Topics: Axons; Nerve Regeneration; Neurons; Central Nervous System; Neurogenesis; Growth Cones
PubMed: 35817655
DOI: 10.1016/j.semcdb.2022.07.001 -
Seminars in Cell & Developmental Biology May 2023Neural networks are constructed through the development of robust axonal projections from individual neurons, which ultimately establish connections with their targets.... (Review)
Review
Neural networks are constructed through the development of robust axonal projections from individual neurons, which ultimately establish connections with their targets. In most animals, developing axons assemble in bundles to navigate collectively across various areas within the central nervous system or the periphery, before they separate from these bundles in order to find their specific targets. These processes, called fasciculation and defasciculation respectively, were thought for many years to be controlled chemically: while guidance cues may attract or repulse axonal growth cones, adhesion molecules expressed at the surface of axons mediate their fasciculation. Recently, an additional non-chemical parameter, the mechanical longitudinal tension of axons, turned out to play a role in axon fasciculation and defasciculation, through zippering and unzippering of axon shafts. In this review, we present an integrated view of the currently known chemical and mechanical control of axon:axon dynamic interactions. We highlight the facts that the decision to cross or not to cross another axon depends on a combination of chemical, mechanical and geometrical parameters, and that the decision to fasciculate/defasciculate through zippering/unzippering relies on the balance between axon:axon adhesion and their mechanical tension. Finally, we speculate about possible functional implications of zippering-dependent axon shaft fasciculation, in the collective migration of axons, and in the sorting of subpopulations of axons.
Topics: Animals; Fasciculation; Axon Fasciculation; Axons; Neurons; Central Nervous System
PubMed: 35810068
DOI: 10.1016/j.semcdb.2022.06.014