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Trends in Neurosciences Oct 2014It is widely recognized that severed axons in the adult central nervous system (CNS) have limited capacity to regenerate. However, mounting evidence from studies of CNS... (Review)
Review
It is widely recognized that severed axons in the adult central nervous system (CNS) have limited capacity to regenerate. However, mounting evidence from studies of CNS injury response and repair is challenging the prevalent view that the adult mammalian CNS is incapable of structural reorganization to adapt to an altered environment. Animal studies demonstrate the potential to achieve significant anatomical repair and functional recovery following CNS injury by manipulating axon growth regulators alone or in combination with activity-dependent strategies. With a growing understanding of the cellular and molecular mechanisms regulating axon plasticity, and the availability of new experimental tools to map detour circuits of functional importance, directing circuit rewiring to promote functional recovery may be achieved.
Topics: Animals; Axons; Central Nervous System; Mammals; Nerve Net; Neural Pathways; Neuronal Plasticity; Recovery of Function
PubMed: 25218468
DOI: 10.1016/j.tins.2014.08.008 -
Traffic (Copenhagen, Denmark) May 2006A substantial number of studies over a period of four decades have indicated that axons contain mRNAs and ribosomes, and are metabolically active in synthesizing... (Review)
Review
A substantial number of studies over a period of four decades have indicated that axons contain mRNAs and ribosomes, and are metabolically active in synthesizing proteins locally. For the most part, little attention has been paid to these findings until recently when the concept of targeting of specific mRNAs and translation in subcellular domains in polarized cells emerged to contribute to the likelihood and acceptance of mRNA targeting to axons as well. Trans-acting factor proteins bind to cis-acting sequences in the untranslated region of mRNAs integrated in ribonucleoprotein (RNPs) complexes determine its targeting in neurons. In vitro studies in immature axons have shown that molecular motors proteins (kinesins and myosins) associate to RNPs suggesting they would participate in its transport to growth cones. Tau and actin mRNAs are transported as RNPs, and targeted to axons as well as ribosomes. Periaxoplasmic ribosomal plaques (PARPs), which are systematically distributed discrete peripheral ribosome-containing, actin-rich formations in myelinated axons, also are enriched with actin and myosin Va mRNAs and additional regulatory proteins. The localization of mRNAs in PARPs probably means that PARPs are local centers of translational activity, and that these domains are the final destination in the axon compartment for targeted macromolecular traffic originating in the cell body. The role of glial cells as a potentially complementary source of axonal mRNAs and ribosomes is discussed in light of early reports and recent ultrastructural observations related to the possibility of glial-axon trans-endocytosis.
Topics: Animals; Axons; Humans; RNA
PubMed: 16643274
DOI: 10.1111/j.1600-0854.2006.00405.x -
Current Opinion in Neurobiology Aug 2018The actin cytoskeleton in neurons plays critical roles in axonal growth and synaptic organization. Until recently, most studies on axonal actin were limited to terminal... (Review)
Review
The actin cytoskeleton in neurons plays critical roles in axonal growth and synaptic organization. Until recently, most studies on axonal actin were limited to terminal growth cones or synapses, whereas the organization of actin along the shaft of the axon was relatively ignored. However, experiments using super-resolution microscopy and live imaging have revealed previously unknown actin structures along the axonal shaft, such as periodic 'actin rings' circumferentially wrapping underneath the plasma membrane and dynamic actin pools deeper within the axon shaft (termed actin 'hotspots' and 'trails'). In this short review, we highlight some open questions that have surfaced as a direct result of these discoveries.
Topics: Actins; Animals; Axons; Cell Membrane
PubMed: 30005298
DOI: 10.1016/j.conb.2018.06.012 -
The Journal of Cell Biology Sep 2013Proper brain wiring during development is pivotal for adult brain function. Neurons display a high degree of polarization both morphologically and functionally, and this... (Review)
Review
Proper brain wiring during development is pivotal for adult brain function. Neurons display a high degree of polarization both morphologically and functionally, and this polarization requires the segregation of mRNA, proteins, and lipids into the axonal or somatodendritic domains. Recent discoveries have provided insight into many aspects of the cell biology of axonal development including axon specification during neuronal polarization, axon growth, and terminal axon branching during synaptogenesis.
Topics: Animals; Axons; Cell Physiological Phenomena; Humans; Neurons; Neurosciences; Signal Transduction
PubMed: 24043699
DOI: 10.1083/jcb.201305098 -
Progress in Neurobiology Nov 2009Although virtually ignored in the literature until recently, the process of 'stretch growth of integrated axon tracts' is perhaps the most remarkable axon growth... (Review)
Review
Although virtually ignored in the literature until recently, the process of 'stretch growth of integrated axon tracts' is perhaps the most remarkable axon growth mechanism of all. This process can extend axons at seemingly impossible rates without the aid of chemical cues or even growth cones. As animals grow, the organization and extremely rapid expansion of the nervous system appears to be directed purely by mechanical forces on axon tracts. This review provides the first glimpse of the astonishing features of axon tracts undergoing stretch growth and how this natural process can be exploited to facilitate repair of the damaged nervous system.
Topics: Animals; Axons; Growth Cones; Nerve Regeneration; Nervous System Diseases; Neurons; Stress, Mechanical
PubMed: 19664679
DOI: 10.1016/j.pneurobio.2009.07.006 -
Journal of Anatomy Feb 1999Most nerves are attached to the neuraxis by rootlets. The CNS-PNS transitional zone (TZ) is that length of rootlet containing both central and peripheral nervous tissue.... (Review)
Review
Most nerves are attached to the neuraxis by rootlets. The CNS-PNS transitional zone (TZ) is that length of rootlet containing both central and peripheral nervous tissue. The 2 tissues are separated by a very irregular but clearly defined interface, consisting of the surface of the astrocytic tissue comprising the central component of the TZ. Central to this, myelin sheaths are formed by oligodendrocytes and the supporting tissue is astrocytic. Peripheral to it, sheaths are formed by Schwann cells which are enveloped in endoneurium. The features of transitional nodes are a composite of those of central and peripheral type. The interface is penetrated only by axons. It is absent at first. It is formed by growth of processes into the axon bundle from glial cell bodies around its perimeter. These form a barrier across the bundle which fully segregates prospectively myelinated axons. Rat spinal dorsal root TZs have been used extensively to study CNS axon regeneration. The CNS part of the TZ responds to primary afferent axon degeneration and to regenerating axons in ways which constitute a satisfactory model of the gliotic tissue response which occurs in CNS lesions. It undergoes gliosis and the gliotic TZ tissue expands distally along the root. In mature animals axons can regenerate satisfactorily through the endoneurial tubes of the root but cease growth on reaching the gliotic tissue. The general objective of experimental studies is to achieve axon regeneration from the PNS through this outgrowth and into the dorsal spinal cord. Since immature tissue has a greater capacity for regeneration than that of the adult, one approach includes the transplantation of embryonic or fetal dorsal root ganglia into the locus of an extirpated adult ganglion. Axons grow centrally from the transplanted ganglion cells and some enter the cord. Other approaches include alteration of the TZ environment to facilitate axon regeneration, for example, by the application of tropic, trophic, or other molecular factors, and also by transplantation of cultured olfactory ensheathing cells (OECs) into the TZ region. OECs, by association with growing axons, facilitate their extensive regeneration into the cord. Unusually, ventral motoneuron axons may undergo some degree of unaided CNS regeneration. When interrupted in the spinal cord white matter, some grow out to the ventral rootlet TZ and thence distally in the PNS. The DRTZ is especially useful for quantitative studies on regeneration. Since the tissue is anisometric, individual parameters such as axon numbers, axon size and glial ensheathment can be readily measured and compared in the CNS and PNS environments, thereby yielding indices of regeneration across the interface for different sets of experimental conditions.
Topics: Animals; Astrocytes; Axons; Central Nervous System; Humans; Microscopy, Electron; Nerve Regeneration; Peripheral Nervous System; Schwann Cells; Spinal Cord
PubMed: 10337949
DOI: 10.1046/j.1469-7580.1999.19420161.x -
Translational Vision Science &... Apr 2023Axons depend on long-range transport of proteins and organelles which increases susceptibility to metabolic stress in disease. The axon initial segment (AIS) is...
PURPOSE
Axons depend on long-range transport of proteins and organelles which increases susceptibility to metabolic stress in disease. The axon initial segment (AIS) is particularly vulnerable due to the high bioenergetic demand of action potential generation. Here, we prepared retinal ganglion cells derived from human embryonic stem cells (hRGCs) to probe how axonal stress alters AIS morphology.
METHODS
hRGCs were cultured on coverslips or microfluidic platforms. We assayed AIS specification and morphology by immunolabeling against ankyrin G (ankG), an axon-specific protein, and postsynaptic density 95 (PSD-95), a dendrite-specific protein. Using microfluidic platforms that enable fluidic isolation, we added colchicine to the axon compartment to lesion axons. We verified axonopathy by measuring the anterograde axon transport of cholera toxin subunit B and immunolabeling against cleaved caspase 3 (CC3) and phosphorylated neurofilament H (SMI-34). We determined the influence of axon injury on AIS morphology by immunolabeling samples against ankG and measuring AIS distance from soma and length.
RESULTS
Based on measurements of ankG and PSD-95 immunolabeling, microfluidic platforms promote the formation and separation of distinct somatic-dendritic versus axonal compartments in hRGCs compared to coverslip cultures. Chemical lesioning of axons by colchicine reduced hRGC anterograde axon transport, increased varicosity density, and enhanced expression of CC3 and SMI-34. Interestingly, we found that colchicine selectively affected hRGCs with axon-carrying dendrites by reducing AIS distance from somas and increasing length, thus suggesting reduced capacity to maintain excitability.
CONCLUSIONS
Thus, microfluidic platforms promote polarized hRGCs that enable modeling of axonopathy.
TRANSLATIONAL RELEVANCE
Microfluidic platforms may be used to assay compartmentalized degeneration that occurs during glaucoma.
Topics: Humans; Retinal Ganglion Cells; Microfluidics; Axons; Action Potentials
PubMed: 37010860
DOI: 10.1167/tvst.12.4.1 -
Experimental Neurology Aug 2013Parkinson's disease (PD) is the most common neurodegenerative disease of the basal ganglia. Like other adult-onset neurodegenerative disorders, it is without a treatment... (Review)
Review
Parkinson's disease (PD) is the most common neurodegenerative disease of the basal ganglia. Like other adult-onset neurodegenerative disorders, it is without a treatment that forestalls its chronic progression. Efforts to develop disease-modifying therapies to date have largely focused on the prevention of degeneration of the neuron soma, with the tacit assumption that such approaches will forestall axon degeneration as well. We herein propose that future efforts to develop neuroprotection for PD may benefit from a shift in focus to the distinct mechanisms that underlie axon degeneration. We review evidence from human post-mortem studies, functional neuroimaging, genetic causes of the disease and neurotoxin models that axon degeneration may be the earliest feature of the disease, and it may therefore be the most appropriate target for early intervention. In addition, we present evidence that the molecular mechanisms of degeneration of axons are separate and distinct from those of neuron soma. Progress is being made in understanding these mechanisms, and they provide possible new targets for therapeutic intervention. We also suggest that the potential for axon re-growth in the adult central nervous system has perhaps been underestimated, and it offers new avenues for neurorestoration. In conclusion, we propose that a new focus on the neurobiology of axons, their molecular pathways of degeneration and growth, will offer novel opportunities for neuroprotection and restoration in the treatment of PD and other neurodegenerative diseases.
Topics: Animals; Axons; Humans; Nerve Degeneration; Parkinson Disease
PubMed: 22285449
DOI: 10.1016/j.expneurol.2012.01.011 -
Cell Adhesion & Migration 2013The peripheral axons of vertebrate tactile somatosensory neurons travel long distances from ganglia just outside the central nervous system to the skin. Once in the skin... (Review)
Review
The peripheral axons of vertebrate tactile somatosensory neurons travel long distances from ganglia just outside the central nervous system to the skin. Once in the skin these axons form elaborate terminals whose organization must be regionally patterned to detect and accurately localize different kinds of touch stimuli. This review describes key studies that identified choice points for somatosensory axon growth cones and the extrinsic molecular cues that function at each of those steps. While much has been learned in the past 20 years about the guidance of these axons, there is still much to be learned about how the peripheral axons of different kinds of somatosensory neurons adopt different trajectories and form specific terminal structures.
Topics: Animals; Axons; Gene Expression Regulation, Developmental; Morphogenesis; Skin
PubMed: 23670092
DOI: 10.4161/cam.25000 -
Neurobiology of Disease Dec 2013Axonal injury and degeneration, whether primary or secondary, contribute to the morbidity and mortality seen in many acquired and inherited central nervous system (CNS)... (Review)
Review
Axonal injury and degeneration, whether primary or secondary, contribute to the morbidity and mortality seen in many acquired and inherited central nervous system (CNS) and peripheral nervous system (PNS) disorders, such as traumatic brain injury, spinal cord injury, cerebral ischemia, neurodegenerative diseases, and peripheral neuropathies. The calpain family of proteases has been mechanistically linked to the dysfunction and degeneration of axons. While the direct mechanisms by which transection, mechanical strain, ischemia, or complement activation trigger intra-axonal calpain activity are likely different, the downstream effects of unregulated calpain activity may be similar in seemingly disparate diseases. In this review, a brief examination of axonal structure is followed by a focused overview of the calpain family. Finally, the mechanisms by which calpains may disrupt the axonal cytoskeleton, transport, and specialized domains (axon initial segment, nodes, and terminals) are discussed.
Topics: Axons; Brain Injuries; Calpain; Humans; Spinal Cord Injuries
PubMed: 23969238
DOI: 10.1016/j.nbd.2013.08.010