-
Molecular and Cellular Neurosciences Jun 2023The endoplasmic reticulum (ER) is the largest membrane compartment within eukaryotic cells and is emerging as a key coordinator of many cellular processes. The ER can... (Review)
Review
The endoplasmic reticulum (ER) is the largest membrane compartment within eukaryotic cells and is emerging as a key coordinator of many cellular processes. The ER can modulate local calcium fluxes and communicate with other organelles like the plasma membrane. The importance of ER in neuronal processes such as neurite growth, axon repair and neurotransmission has recently gained much attention. In this review, we highlight the importance of the ER tubular network in axonal homeostasis and discuss how the generation and maintenance of the thin tubular ER network in axons and synapses, requires a cooperative effort of ER-shaping proteins, cytoskeleton and autophagy processes.
Topics: Neurons; Axons; Neurites; Microtubules; Endoplasmic Reticulum; Autophagy; Endoplasmic Reticulum Stress
PubMed: 36781033
DOI: 10.1016/j.mcn.2023.103822 -
Zhejiang Da Xue Xue Bao. Yi Xue Ban =... Aug 2020Different from neurons in the peripheral nervous system, mature neurons in the mammalian central nervous system often fail to regenerate after injury. Recent studies... (Review)
Review
Different from neurons in the peripheral nervous system, mature neurons in the mammalian central nervous system often fail to regenerate after injury. Recent studies have found that calcium transduction, injury signaling, mitochondrial transportation, cytoskeletal remodeling and protein synthesis play essential roles in axon regeneration. Firstly, axon injury increases the intracellular concentration of calcium, and initiates the injury signaling pathways including cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) and dual leucine kinase (DLK), which are found to promote axon regeneration in multiple animal injury models. The second step for axonal regrowth is to rebuild growth cones. Overexpressing proteins that promote dynamics of microtubules and actin filaments is beneficial for the reassembly of cytoskeletons and initiation of new growth cones. Thirdly, mitochondria, the power factory for cells, also play important roles in growth cone formation and axonal extension. The last but not the least important step is the regulation of gene transcription and protein translation to sustain the regrowth of axons. This review summarizes important findings revealing the functions and mechanisms of these biological progresses.
Topics: Animals; Axons; Growth Cones; Models, Animal; Nerve Regeneration; Neurology; Research
PubMed: 32985164
DOI: 10.3785/j.issn.1008-9292.2020.08.15 -
International Journal of Molecular... 2012Axonal transport and neuronal survival depend critically on active transport and axon integrity both for supplying materials and communication to different domains of... (Review)
Review
Axonal transport and neuronal survival depend critically on active transport and axon integrity both for supplying materials and communication to different domains of the cell body. All these actions are executed through cytoskeleton, transport and regulatory elements that appear to be disrupted in neurodegenerative diseases. Motor-driven transport both supplies and clears distal cellular portions with proteins and organelles. This transport is especially relevant in projection and motor neurons, which have long axons to reach the farthest nerve endings. Thus, any disturbance of axonal transport may have severe consequences for neuronal function and survival. A growing body of literature indicates the presence of alterations to the motor molecules machinery, not only in expression levels and phosphorylation, but also in their subcellular distribution within populations of neurons, which are selectively affected in the course of neurodegenerative diseases. The implications of this altered subcellular localization and how this affects axon survival and neuronal death still remain poorly understood, although several hypotheses have been suggested. Furthermore, cytoskeleton and transport element localization can be selectively disrupted in some disorders suggesting that specific loss of the axonal functionality could be a primary hallmark of the disorder. This can lead to axon degeneration and neuronal death either directly, through the functional absence of essential axonal proteins, or indirectly, through failures in communication among different cellular domains. This review compares the localization of cytoskeleton and transport elements in some neurodegenerative disorders to ask what aspects may be essential for axon survival and neuronal death.
Topics: Axonal Transport; Axons; Brain Injuries; Cell Survival; Cytoskeleton; Humans; Motor Neurons; Neurodegenerative Diseases
PubMed: 22606038
DOI: 10.3390/ijms13045195 -
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 -
Developmental Neurobiology Dec 2011Understanding axon regenerative failure remains a major goal in neuroscience, and reversing this failure remains a major goal for clinical neurology. Although an... (Review)
Review
Understanding axon regenerative failure remains a major goal in neuroscience, and reversing this failure remains a major goal for clinical neurology. Although an inhibitory central nervous system environment clearly plays a role, focus on molecular pathways within neurons has begun to yield fruitful insights. Initial steps forward investigated the receptors and signaling pathways immediately downstream of environmental cues, but recent work has also shed light on transcriptional control mechanisms that regulate intrinsic axon growth ability, presumably through whole cassettes of gene target regulation. Here we will discuss transcription factors that regulate neurite growth in vitro and in vivo, including p53, SnoN, E47, cAMP-responsive element binding protein (CREB), signal transducer and activator of transcription 3 (STAT3), nuclear factor of activated T cell (NFAT), c-Jun activating transcription factor 3 (ATF3), sex determining region Ybox containing gene 11 (Sox11), nuclear factor κ-light chain enhancer of activated B cells (NFκB), and Krüppel-like factors (KLFs). Revealing the similarities and differences among the functions of these transcription factors may further our understanding of the mechanisms of transcriptional regulation in axon growth and regeneration.
Topics: Animals; Axons; Neurons; Regeneration; Signal Transduction; Transcription Factors
PubMed: 21674813
DOI: 10.1002/dneu.20934 -
Nature Communications Jun 2023Second messengers, including cAMP, cGMP and Ca are often placed in an integrating position to combine the extracellular cues that orient growing axons in the developing...
Second messengers, including cAMP, cGMP and Ca are often placed in an integrating position to combine the extracellular cues that orient growing axons in the developing brain. This view suggests that axon repellents share the same set of cellular messenger signals and that axon attractants evoke opposite cAMP, cGMP and Ca changes. Investigating the confinement of these second messengers in cellular nanodomains, we instead demonstrate that two repellent cues, ephrin-A5 and Slit1, induce spatially segregated signals. These guidance molecules activate subcellular-specific second messenger crosstalk, each signaling network controlling distinct axonal morphology changes in vitro and pathfinding decisions in vivo.
Topics: Axons; Second Messenger Systems; Cyclic GMP; Signal Transduction
PubMed: 37369692
DOI: 10.1038/s41467-023-39516-z -
Current Opinion in Neurobiology Aug 2016Myelination of axons in the central nervous system results from the remarkable ability of oligodendrocytes to wrap multiple axons with highly specialized membrane.... (Review)
Review
Myelination of axons in the central nervous system results from the remarkable ability of oligodendrocytes to wrap multiple axons with highly specialized membrane. Because myelin membrane grows as it ensheaths axons, cytoskeletal rearrangements that enable ensheathment must be coordinated with myelin production. Because the myelin sheaths of a single oligodendrocyte can differ in thickness and length, mechanisms that coordinate axon ensheathment with myelin growth likely operate within individual oligodendrocyte processes. Recent studies have revealed new information about how assembly and disassembly of actin filaments helps drive the leading edge of nascent myelin membrane around and along axons. Concurrently, other investigations have begun to uncover evidence of communication between axons and oligodendrocytes that can regulate myelin formation.
Topics: Axons; Cell Membrane; Central Nervous System; Myelin Sheath; Oligodendroglia
PubMed: 27152449
DOI: 10.1016/j.conb.2016.04.013 -
Development (Cambridge, England) Sep 2021Since the pioneering work of Ramón y Cajal, scientists have sought to unravel the complexities of axon development underlying neural circuit formation. Micrometer-scale... (Review)
Review
Since the pioneering work of Ramón y Cajal, scientists have sought to unravel the complexities of axon development underlying neural circuit formation. Micrometer-scale axonal growth cones navigate to targets that are often centimeters away. To reach their targets, growth cones react to dynamic environmental cues that change in the order of seconds to days. Proper axon growth and guidance are essential to circuit formation, and progress in imaging has been integral to studying these processes. In particular, advances in high- and super-resolution microscopy provide the spatial and temporal resolution required for studying developing axons. In this Review, we describe how improved microscopy has revolutionized our understanding of axonal development. We discuss how novel technologies, specifically light-sheet and super-resolution microscopy, led to new discoveries at the cellular scale by imaging axon outgrowth and circuit wiring with extreme precision. We next examine how advanced microscopy broadened our understanding of the subcellular dynamics driving axon growth and guidance. We finally assess the current challenges that the field of axonal biology still faces for imaging axons, and examine how future technology could meet these needs.
Topics: Animals; Axons; Growth Cones; Humans; Microscopy
PubMed: 34328171
DOI: 10.1242/dev.199717 -
Current Opinion in Neurology Dec 2014The axon plays a central role in both the injury and repair phases after stroke. This review highlights emerging principles in the study of axonal injury in stroke and... (Review)
Review
PURPOSE OF REVIEW
The axon plays a central role in both the injury and repair phases after stroke. This review highlights emerging principles in the study of axonal injury in stroke and the role of the axon in neural repair after stroke.
RECENT FINDINGS
Ischemic stroke produces a rapid and significant loss of axons in the acute phase. This early loss of axons results from a primary ischemic injury that triggers a wave of calcium signaling, activating proteolytic mechanisms and downstream signaling cascades. A second progressive phase of axonal injury occurs during the subacute period and damages axons that survive the initial ischemic insult but go on to experience a delayed axonal degeneration driven in part by changes in axoglial contact and axonal energy metabolism. Recovery from stroke is dependent on axonal sprouting and reconnection that occurs during a third degenerative/regenerative phase. Despite this central role played by the axon, comparatively little is understood about the molecular pathways that contribute to early and subacute axonal degeneration after stroke. Recent advances in axonal neurobiology and signaling suggest new targets that hold promise as potential molecular therapeutics including axonal calcium signaling, axoglial energy metabolism and cell adhesion as well as retrograde axonal mitogen-activated protein kinase pathways. These novel pathways must be modeled appropriately as the type and severity of axonal injury vary by stroke subtype.
SUMMARY
Stroke-induced injury to axons occurs in three distinct phases each with a unique molecular underpinning. A wealth of new data about the molecular organization and molecular signaling within axons is available but not yet robustly applied to the study of axonal injury after stroke. Identifying the spatiotemporal patterning of molecular pathways within the axon that contribute to injury and repair may offer new therapeutic strategies for the treatment of stroke.
Topics: Animals; Axons; Humans; Nerve Degeneration; Nerve Regeneration; Signal Transduction; Stroke
PubMed: 25364952
DOI: 10.1097/WCO.0000000000000149 -
Neural Development Nov 2019Axons are the slender, cable-like, up to meter-long projections of neurons that electrically wire our brains and bodies. In spite of their challenging morphology, they... (Review)
Review
Axons are the slender, cable-like, up to meter-long projections of neurons that electrically wire our brains and bodies. In spite of their challenging morphology, they usually need to be maintained for an organism's lifetime. This makes them key lesion sites in pathological processes of ageing, injury and neurodegeneration. The morphology and physiology of axons crucially depends on the parallel bundles of microtubules (MTs), running all along to serve as their structural backbones and highways for life-sustaining cargo transport and organelle dynamics. Understanding how these bundles are formed and then maintained will provide important explanations for axon biology and pathology. Currently, much is known about MTs and the proteins that bind and regulate them, but very little about how these factors functionally integrate to regulate axon biology. As an attempt to bridge between molecular mechanisms and their cellular relevance, we explain here the model of local axon homeostasis, based on our own experiments in Drosophila and published data primarily from vertebrates/mammals as well as C. elegans. The model proposes that (1) the physical forces imposed by motor protein-driven transport and dynamics in the confined axonal space, are a life-sustaining necessity, but pose a strong bias for MT bundles to become disorganised. (2) To counterbalance this risk, MT-binding and -regulating proteins of different classes work together to maintain and protect MT bundles as necessary transport highways. Loss of balance between these two fundamental processes can explain the development of axonopathies, in particular those linking to MT-regulating proteins, motors and transport defects. With this perspective in mind, we hope that more researchers incorporate MTs into their work, thus enhancing our chances of deciphering the complex regulatory networks that underpin axon biology and pathology.
Topics: Animals; Axons; Homeostasis; Microtubules
PubMed: 31706327
DOI: 10.1186/s13064-019-0134-0