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Molecular and Cellular Neurosciences Oct 2017Nerve growth cones, the dilated tip of developing axons, are equipped with exquisite abilities to sense environmental cues and to move rapidly through complex terrains... (Review)
Review
Nerve growth cones, the dilated tip of developing axons, are equipped with exquisite abilities to sense environmental cues and to move rapidly through complex terrains of developing brain, leading the axons to their specific targets for precise neuronal wiring. The actin cytoskeleton is the major component of the growth cone that powers its directional motility. Past research has provided significant insights into the mechanisms by which growth cones translate extracellular signals into directional migration. In this review, we summarize the actin-based mechanisms underlying directional growth cone motility, examine novel findings, and discuss the outstanding questions concerning the actin-based growth cone behaviors.
Topics: Actins; Animals; Axons; Cell Adhesion; Cell Movement; Growth Cones; Humans; Neurons
PubMed: 28268126
DOI: 10.1016/j.mcn.2017.03.001 -
Journal of Biosciences 2020For more than a century, mechanical forces have been predicted to govern many biological processes during development, both at the cellular level and in tissue... (Review)
Review
For more than a century, mechanical forces have been predicted to govern many biological processes during development, both at the cellular level and in tissue homeostasis. The cytomechanics of the thin and highly extended neuronal axons have intrigued generations of biologists and biophysicists. However, our knowledge of the biophysics of neurite growth and development is far from complete. Due to its motile behavior and its importance in axonal pathfinding, the growth cone has received significant attention. A considerable amount of information is now available on the spatiotemporal regulation of biochemical signaling and remodeling of the growth cone cytoskeleton. However, the cytoskeletal organization and dynamics in the axonal shaft were poorly explored until recently. Driven by advances in microscopy, there has been a surge of interest in the axonal cytoskeleton in the last few years. A major emerging area of investigation is the relationship between the axonal cytoskeleton and the diverse mechanobiological responses of neurons. This review attempts to summarize our current understanding of the axonal cytoskeleton and its critical role in governing axonal mechanics in the context of neuronal development.
Topics: Actin Cytoskeleton; Animals; Biomechanical Phenomena; Growth Cones; Humans; Intermediate Filaments; Mechanotransduction, Cellular; Microtubule-Associated Proteins; Microtubules; Neurogenesis; Neuronal Plasticity; Synapses; Synaptic Vesicles
PubMed: 32385223
DOI: No ID Found -
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 -
Journal of Neurochemistry Apr 2014Motile growth cones lead growing axons through developing tissues to synaptic targets. These behaviors depend on the organization and dynamics of actin filaments that... (Review)
Review
Motile growth cones lead growing axons through developing tissues to synaptic targets. These behaviors depend on the organization and dynamics of actin filaments that fill the growth cone leading margin [peripheral (P-) domain]. Actin filament organization in growth cones is regulated by actin-binding proteins that control all aspects of filament assembly, turnover, interactions with other filaments and cytoplasmic components, and participation in producing mechanical forces. Actin filament polymerization drives protrusion of sensory filopodia and lamellipodia, and actin filament connections to the plasma membrane link the filament network to adhesive contacts of filopodia and lamellipodia with other surfaces. These contacts stabilize protrusions and transduce mechanical forces generated by actomyosin activity into traction that pulls an elongating axon along the path toward its target. Adhesive ligands and extrinsic guidance cues bind growth cone receptors and trigger signaling activities involving Rho GTPases, kinases, phosphatases, cyclic nucleotides, and [Ca++] fluxes. These signals regulate actin-binding proteins to locally modulate actin polymerization, interactions, and force transduction to steer the growth cone leading margin toward the sources of attractive cues and away from repellent guidance cues.
Topics: Actin Cytoskeleton; Actins; Animals; Cell Adhesion; Cell Movement; Growth Cones; Humans; Microfilament Proteins; Pseudopodia
PubMed: 24164353
DOI: 10.1111/jnc.12506 -
International Journal of Molecular... Jul 2020The development of neural circuits is a complex process that relies on the proper navigation of axons through their environment to their appropriate targets. While... (Review)
Review
The development of neural circuits is a complex process that relies on the proper navigation of axons through their environment to their appropriate targets. While axon-environment and axon-target interactions have long been known as essential for circuit formation, communication between axons themselves has only more recently emerged as another crucial mechanism. Trans-axonal signaling governs many axonal behaviors, including fasciculation for proper guidance to targets, defasciculation for pathfinding at important choice points, repulsion along and within tracts for pre-target sorting and target selection, repulsion at the target for precise synaptic connectivity, and potentially selective degeneration for circuit refinement. This review outlines the recent advances in identifying the molecular mechanisms of trans-axonal signaling and discusses the role of axon-axon interactions during the different steps of neural circuit formation.
Topics: Animals; Axons; Fasciculation; Growth Cones; Neural Conduction; Signal Transduction
PubMed: 32708320
DOI: 10.3390/ijms21145170 -
Neuroscience Bulletin Aug 2014Precise modulation of the cytoskeleton is involved in a variety of cellular processes including cell division, migration, polarity, and adhesion. In developing... (Review)
Review
Precise modulation of the cytoskeleton is involved in a variety of cellular processes including cell division, migration, polarity, and adhesion. In developing post-mitotic neurons, extracellular guidance cues not only trigger signaling cascades that act at a distance to indirectly regulate microtubule distribution, and assembly and disassembly in the growth cone, but also directly modulate microtubule stability and dynamics through coupling of guidance receptors with microtubules to control growth-cone turning. Microtubule-associated proteins including classical microtubule-associated proteins and microtubule plus-end tracking proteins are required for modulating microtubule dynamics to influence growth-cone steering. Multiple key signaling components, such as calcium, small GTPases, glycogen synthase kinase-3β, and c-Jun N-terminal kinase, link upstream signal cascades to microtubule stability and dynamics in the growth cone to control axon outgrowth and projection. Understanding the functions and regulation of microtubule dynamics in the growth cone provides new insights into the molecular mechanisms of axon guidance.
Topics: Animals; Axons; Growth Cones; Humans; Microtubule-Associated Proteins; Microtubules; Nerve Growth Factors; Signal Transduction; Tubulin
PubMed: 24968808
DOI: 10.1007/s12264-014-1444-6 -
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 -
Molecular Biology of the Cell Jun 2022Neuron navigator 1 (Nav1) is a cytoskeleton-associated protein expressed during brain development that is necessary for proper neuritogenesis, but the underlying...
Neuron navigator 1 (Nav1) is a cytoskeleton-associated protein expressed during brain development that is necessary for proper neuritogenesis, but the underlying mechanisms are poorly understood. Here we show that Nav1 is present in elongating axon tracts during mouse brain embryogenesis. We found that depletion of Nav1 in cultured neurons disrupts growth cone morphology and neurotrophin-stimulated neuritogenesis. In addition to regulating both F-actin and microtubule properties, Nav1 promotes actin-rich membrane ruffles in the growth cone and promotes macropinocytosis at those membrane ruffles, including internalization of the TrkB receptor for the neurotrophin brain-derived neurotropic factor (BDNF). Growth cone macropinocytosis is important for downstream signaling, neurite targeting, and membrane recycling, implicating Nav1 in one or more of these processes. Depletion of Nav1 also induces transient membrane blebbing via disruption of signaling in the Rho GTPase signaling pathway, supporting the novel role of Nav1 in dynamic actin-based membrane regulation at the cell periphery. These data demonstrate that Nav1 works at the interface of microtubules, actin, and plasma membrane to organize the cell periphery and promote uptake of growth and guidance cues to facilitate neural morphogenesis during development.
Topics: Actins; Animals; Cells, Cultured; Cytoskeletal Proteins; Growth Cones; Mice; Microtubules; Nerve Growth Factors; Neurons; Receptors, Nerve Growth Factor
PubMed: 35352947
DOI: 10.1091/mbc.E21-12-0623 -
Cold Spring Harbor Perspectives in... Mar 2011Axon outgrowth and guidance to the proper target requires the coordination of filamentous (F)-actin and microtubules (MTs), the dynamic cytoskeletal polymers that... (Review)
Review
Axon outgrowth and guidance to the proper target requires the coordination of filamentous (F)-actin and microtubules (MTs), the dynamic cytoskeletal polymers that promote shape change and locomotion. Over the past two decades, our knowledge of the many guidance cues, receptors, and downstream signaling cascades involved in neuronal outgrowth and guidance has increased dramatically. Less is known, however, about how those cascades of information converge and direct appropriate remodeling and interaction of cytoskeletal polymers, the ultimate effectors of movement and guidance. During development, much of the communication that occurs between environmental guidance cues and the cytoskeleton takes place at the growing tip of the axon, the neuronal growth cone. Several articles on this topic focus on the "input" to the growth cone, the myriad of receptor types, and their corresponding cognate ligands. Others investigate the signaling cascades initiated by receptors and propagated by second messenger pathways (i.e., kinases, phosphatases, GTPases). Ultimately, this plethora of information converges on proteins that associate directly with the actin and microtubule cytoskeletons. The role of these cytoskeletal-associated proteins, as well as the cytoskeleton itself in axon outgrowth and guidance, is the subject of this article.
Topics: Actins; Animals; Axons; Cell Communication; Cell Movement; Cytoskeletal Proteins; Cytoskeleton; Growth Cones; Humans; Models, Biological; Second Messenger Systems
PubMed: 21106647
DOI: 10.1101/cshperspect.a001800 -
Journal of Anatomy Apr 2018A prominent anatomical feature of the peripheral nervous system is the segmentation of mixed (motor, sensory and autonomic) spinal nerves alongside the spinal cord.... (Review)
Review
A prominent anatomical feature of the peripheral nervous system is the segmentation of mixed (motor, sensory and autonomic) spinal nerves alongside the spinal cord. During early development their axon growth cones avoid the developing vertebral elements by traversing the anterior/cranial half of each somite-derived sclerotome, so ensuring the separation of spinal nerves from vertebral bones as axons extend towards their peripheral targets. A glycoprotein expressed on the surface of posterior half-sclerotome cells confines growth cones to the anterior half-sclerotomes by contact repulsion. A closely similar glycoprotein is expressed in avian and mammalian grey matter, where we hypothesize it may have evolved to regulate neural plasticity in birds and mammals.
Topics: Animals; Body Patterning; Chick Embryo; Growth Cones; Humans; Mice; Nerve Growth Factor; Somites; Spinal Cord; Spinal Nerves; Spine
PubMed: 29063597
DOI: 10.1111/joa.12714