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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 -
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 -
The American Journal of Pathology Jan 2018The mechanisms that underlie recovery after injury of the central nervous system have rarely been definitively established. Axon regrowth remains the major prerequisite... (Review)
Review
The mechanisms that underlie recovery after injury of the central nervous system have rarely been definitively established. Axon regrowth remains the major prerequisite for plasticity, regeneration, circuit formation, and eventually functional recovery. The attributed functional relevance of axon regrowth, however, will depend on several subsequent conditional neurobiological modifications, including myelination and synapse formation, but also pruning of aberrant connectivity. Despite the ability to revamp axon outgrowth by altering an increasing number of extracellular and intracellular targets, disentangling which axons are responsible for the recovery of function from those that are functionally silent, or even contributing to aberrant functions, represents a pertinent void in our understanding, challenging the intuitive translational link between anatomical and functional regeneration. Anatomic hallmarks of regeneration are not static and are largely activity dependent. Herein, we survey mechanisms leading to the formation of dystrophic growth cone at the injured axonal tip, the subsequent axonal dieback, and the molecular determinants of axon growth, plasticity, and regeneration in the context of spinal cord injury.
Topics: Animals; Axons; Growth Cones; Nerve Regeneration; Neurogenesis; Neuronal Plasticity; Recovery of Function; Spinal Cord Injuries
PubMed: 29030051
DOI: 10.1016/j.ajpath.2017.09.005 -
Current Opinion in Neurobiology Aug 2019Ion channels are microscopic pore proteins in the membrane that open and close in response to chemical and electrical stimuli. This simple concept underlies rapid... (Review)
Review
Ion channels are microscopic pore proteins in the membrane that open and close in response to chemical and electrical stimuli. This simple concept underlies rapid electrical signaling in the brain as well as several important aspects of neural plasticity. Although the soma accounts for less than 1% of many neurons by membrane area, it has been the major site of measuring ion channel function. However, the axon is one of the longest processes found in cellular biology and hosts a multitude of critical signaling functions in the brain. Not only does the axon initiate and rapidly propagate action potentials (APs) across the brain but it also forms the presynaptic terminals that convert these electrical inputs into chemical outputs. Here, we review recent advances in the physiological role of ion channels within the diverse landscape of the axon and presynaptic terminals.
Topics: Action Potentials; Axons; Ion Channels; Neurons; Presynaptic Terminals
PubMed: 30784979
DOI: 10.1016/j.conb.2019.01.020 -
Trends in Neurosciences Mar 2009Axon-guidance-pathway molecules are involved in connectivity and repair throughout life (beyond guiding brain wiring during fetal development). One study found that... (Review)
Review
Axon-guidance-pathway molecules are involved in connectivity and repair throughout life (beyond guiding brain wiring during fetal development). One study found that variations (single-nucleotide polymorphisms [SNPs]) in axon-guidance-pathway genes were predictive of three Parkinson's disease (PD) outcomes (susceptibility, survival free of PD and age at onset of PD) in genome-wide association (GWA) datasets. The axon-guidance-pathway genes DCC, EPHB1, NTNG1, SEMA5A and SLIT3 were represented by SNPs predicting PD outcomes. Beyond GWA analyses, we also present relevant neurobiological roles of these axon-guidance-pathway molecules and consider mechanisms by which abnormal axon-guidance-molecule signaling can cause loss of connectivity and, ultimately, PD. Novel drugs and treatments could emerge from this new understanding.
Topics: Animals; Axons; Humans; Neural Pathways; Neurodegenerative Diseases; Neurons; Synapses
PubMed: 19162339
DOI: 10.1016/j.tins.2008.11.006 -
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 -
Molecules and Cells Jan 2017When peripheral axons are damaged, neuronal injury signaling pathways induce transcriptional changes that support axon regeneration and consequent functional recovery.... (Review)
Review
When peripheral axons are damaged, neuronal injury signaling pathways induce transcriptional changes that support axon regeneration and consequent functional recovery. The recent development of bioinformatics techniques has allowed for the identification of many of the regeneration-associated genes that are regulated by neural injury, yet it remains unclear how global changes in transcriptome are coordinated. In this article, we review recent studies on the epigenetic mechanisms orchestrating changes in gene expression in response to nerve injury. We highlight the importance of epigenetic mechanisms in discriminating efficient axon regeneration in the peripheral nervous system and very limited axon regrowth in the central nervous system and discuss the therapeutic potential of targeting epigenetic regulators to improve neural recovery.
Topics: Axons; Epigenesis, Genetic; Humans; Nerve Regeneration; Signal Transduction; Trauma, Nervous System
PubMed: 28152303
DOI: 10.14348/molcells.2017.2311 -
Cold Spring Harbor Perspectives in... Mar 2022Axons are a unique cellular structure that allows for the communication between neurons. Axon damage compromises neuronal communications and often leads to functional... (Review)
Review
Axons are a unique cellular structure that allows for the communication between neurons. Axon damage compromises neuronal communications and often leads to functional deficits. Thus, developing strategies that promote effective axon regeneration for functional restoration is highly desirable. One fruitful approach is to dissect the regenerative mechanisms used by some types of neurons in both mammalian and nonmammalian systems that exhibit spontaneous regenerative capacity. Additionally, numerous efforts have been devoted to deciphering the barriers that prevent successful axon regeneration in the most regeneration-refractory system-the adult mammalian central nervous system. As a result, several regeneration-promoting strategies have been developed, but significant limitations remain. This review is aimed to summarize historic progression and current understanding of this exciting yet incomplete endeavor.
Topics: Animals; Axons; Central Nervous System; Mammals; Nerve Regeneration; Neurons
PubMed: 34518340
DOI: 10.1101/cshperspect.a040923 -
Brain Research Bulletin Jan 2023Directed outgrowth of axons is fundamental for the establishment of neuronal networks. Axon outgrowth is guided by growth cones, highly motile structures enriched in... (Review)
Review
Directed outgrowth of axons is fundamental for the establishment of neuronal networks. Axon outgrowth is guided by growth cones, highly motile structures enriched in filamentous actin (F-actin) located at the axons' distal tips. Growth cones exploit F-actin-based protrusions to scan the environment for guidance cues, and they contain the sensory apparatus to translate guidance cue information into intracellular signaling cascades. These cascades act upstream of actin-binding proteins (ABP) and thereby control assembly and disassembly of F-actin. Spatiotemporally controlled F-actin dis-/assembly in growth cones steers the axon towards attractants and away from repellents, and it thereby navigates the axon through the developing nervous system. Hence, ABP that control F-actin dynamics emerged as critical regulators of neuronal network formation. In the present review article, we will summarize and discuss current knowledge of the mechanisms that control remodeling of the actin cytoskeleton in growth cones, focusing on recent progress in the field. Further, we will introduce tools and techniques that allow to study actin regulatory mechanism in growth cones.
Topics: Growth Cones; Actins; Actin Cytoskeleton; Axons; Microfilament Proteins
PubMed: 36336143
DOI: 10.1016/j.brainresbull.2022.10.019 -
International Journal For Numerical... Nov 2022We report a computational study of mitochondria transport in a branched axon with two branches of different sizes. For comparison, we also investigate mitochondria...
We report a computational study of mitochondria transport in a branched axon with two branches of different sizes. For comparison, we also investigate mitochondria transport in an axon with symmetric branches and in a straight (unbranched) axon. The interest in understanding mitochondria transport in branched axons is motivated by the large size of arbors of dopaminergic neurons, which die in Parkinson's disease. Since the failure of energy supply of multiple demand sites located in various axonal branches may be a possible reason for the death of these neurons, we were interested in investigating how branching affects mitochondria transport. Besides investigating mitochondria fluxes between the demand sites and mitochondria concentrations, we also studied how the mean age of mitochondria and mitochondria age densities depend on the distance from the soma. We established that if the axon splits into two branches of unequal length, the mean ages of mitochondria and age density distributions in the demand sites are affected by how the mitochondria flux splits at the branching junction (what portion of mitochondria enter the shorter branch and what portion enter the longer branch). However, if the axon splits into two branches of equal length, the mean ages and age densities of mitochondria are independent of how the mitochondria flux splits at the branching junction. This even holds for the case when all mitochondria enter one branch, which is equivalent to a straight axon. Because the mitochondrial membrane potential (which many researchers view as a proxy for mitochondrial health) decreases with mitochondria age, the independence of mitochondria age on whether the axon is symmetrically branched or straight (providing the two axons are of the same length), and on how the mitochondria flux splits at the branching junction, may explain how dopaminergic neurons can sustain very large arbors and still maintain mitochondrial health across branch extremities.
Topics: Neurons; Axons; Mitochondria
PubMed: 36125402
DOI: 10.1002/cnm.3648