Adjacent Axons Research Articles

Abstract T P79: Molecular Disorganization of Axons Adjacent to Subcortical Stroke in Hereditary Endotheliopathy With Retinopathy, Nephropathy, and Stroke; an Imaging to Molecular Neuropathology Correlation

White matter stroke secondary to microvascular injury is common yet the molecular changes that accompany ischemic damage to white matter are poorly understood. MRI imaging studies suggest that abnormalities exist within the white matter adjacent to lacunar infarcts and this may lead to infarct progression through a functional disruption of adjacent axons. Hereditary subcortical stroke syndromes provide a unique opportunity to study the molecular mechanisms of cerebral microvascular disease and its effect on white matter. Here, we examined two autopsy cases of hereditary endotheliopathy with retinopathy, nephropathy and stroke (HERNS) syndrome with severe microvascular ischemic disease in the cerebral white matter to determine the molecular organization of myelin and axons within the cerebral white matter adjacent to lacunar infarcts in these patients. MRI imaging was used to identify regions of prior lacunar infarction or FLAIR hyperintensity. Serial paraffin-embedded sections within these regions were immunolabeled for markers of nodes of Ranvier and paranodes as well as neurofilaments and myelin basic protein and compared to normal-appearing white matter and non-diseased controls. Compared to controls, HERNS cases demonstrate lengthening of paranodes and disrupted nodal staining patterns consistent with a loss of normal axon-oligodendrocyte molecular interactions. These abnormalities of axonal microdomains are present beyond the region of infarction suggested by MRI and H&E sections and occur in areas of FLAIR hyperintensity without frank lacunar infarction. These results indicate there is a peri-infarct in white matter stroke marked by molecular disruption of axons surrounding the infarct that may serve as a new therapeutic target for this currently untreatable form of ischemic stroke.

Oligodendrocytes in neurodegenerative diseases

Oligodendrocyte is a highly specialized glial cell type in the vertebrate central nervous system, which guarantees the long-distance transmission of action potential by producing myelin sheath wrapping adjacent axons. Disrupted myelin and oligodendrocytes are hallmarks of some devastating neurological diseases, such as multiple sclerosis, although their contribution to neurodegeneration in a given disease is still controversial. However, accumulating evidence from clinical studies and genetic animal models implicates oligodendrocyte dysfunction as one of major events in the processes of initiation and progression of neurodegeneration. In this article, we will review recent progress in understanding non-traditional function of oligodendrocytes in neuronal support and protection independent of myelin sheath and its possible contribution to neurodegeneration. Oligodendrocytes play a pivotal role in neurodegenerative diseases among which special emphasis is given to multiple system atrophy and Alzheimer’s disease in this review.

Abstract 86: Expanding The Lacunar Infarct: Molecular Reorganization Of Axons Adjacent To Human White Matter Stroke

White matter stroke compromises approximately 25% of all strokes and accounts for significant disability by directly damaging myelin and axons. Patients presenting with white matter stroke often worsen clinically during the acute presentation. MRI studies demonstrate that white matter stroke lesions often expand in size over time. In part, this may be due to progressive expansion of infarcts through functional disruption of adjacent axons. The function of myelinated axons is dependent on molecular clustering of voltage-gated sodium channels at nodes of Ranvier. This clustering is partly dependent on the interaction with myelinating oligodendrocytes at axonal regions adjacent to nodes, termed paranodes. Here, we examined 10 autopsy cases of patients with lacunar infarcts and 3 controls for the molecular integrity of axonal microdomains adjacent to stroke. Lacunar infarcts were identified using clinical history and H&E sections. Serial sections were labeled for immunofluorescent markers of nodes and paranodes as well as neurofilaments and myelin basic protein. Compared to controls, there is lengthening of paranodes adjacent to white matter stroke consistent with disrupted axon-oligodendrocyte molecular interactions. In addition, immunolabeling for both voltage-gated sodium channels and their cytoskeletal anchors are disrupted in peri-infarct tissue. These abnormalities of axonal microdomains are present in a region larger than the infarct size as measured by H&E. These results indicate that white matter stroke produces functional disorganization of axons adjacent to the traditional lacune. A white matter stroke peri-infarct marked by molecularly disorganized axons provides a new therapeutic target for the treatment of white matter stroke.

Role of pro-brain-derived neurotrophic factor (proBDNF) to mature BDNF conversion in activity-dependent competition at developing neuromuscular synapses

Formation of specific neuronal connections often involves competition between adjacent axons, leading to stabilization of the active terminal, while retraction of the less active ones. The underlying molecular mechanisms remain unknown. We show that activity-dependent conversion of pro-brain-derived neurotrophic factor (proBDNF) to mature (m)BDNF mediates synaptic competition. Stimulation of motoneurons triggers proteolytic conversion of proBDNF to mBDNF at nerve terminals. In Xenopus nerve-muscle cocultures, in which two motoneurons innervate one myocyte, proBDNF-p75(NTR) signaling promotes retraction of the less active terminal, whereas mBDNF-tyrosine-related kinase B (TrkB) p75NTR (p75 neurotrophin receptor) facilitates stabilization of the active one. Thus, proBDNF and mBDNF may serve as potential "punishment" and "reward" signals for inactive and active terminals, respectively, and activity-dependent conversion of proBDNF to mBDNF may regulate synapse elimination.

Retrograde and Wallerian Axonal Degeneration Occur Synchronously after Retinal Ganglion Cell Axotomy

Axonal injury and degeneration are pivotal pathological events in diseases of the nervous system. In the past decade, it has been recognized that the process of axonal degeneration is distinct from somal degeneration and that axoprotective strategies may be distinct from those that protect the soma. Preserving the cell body via neuroprotection cannot improve function if the axon is damaged, because the soma is still disconnected from its target. Therefore, understanding the mechanisms of axonal degeneration is critical for developing new therapeutic interventions for axonal disease treatment. We combined in vivo imaging with a multilaser confocal scanning laser ophthalmoscope and in vivo axotomy with a diode-pumped solid-state laser to assess the time course of Wallerian and retrograde degeneration of unmyelinated retinal ganglion cell axons in living rats for 4 weeks after intraretinal axotomy. Laser injury resulted in reproducible axon loss both distal and proximal to the site of injury. Longitudinal polarization-sensitive imaging of axons demonstrated that Wallerian and retrograde degeneration occurred synchronously. Neurofilament immunostaining of retinal whole-mounts confirmed axonal loss and demonstrated sparing of adjacent axons to the axotomy site. In vivo fluorescent imaging of axonal transport and photobleaching of labeled axons demonstrated that the laser axotomy model did not affect adjacent axon function. These results are consistent with a shared mechanism for Wallerian and retrograde degeneration.

Mechanistic Logic Underlying the Axonal Transport of Cytosolic Proteins

Proteins vital to presynaptic function are synthesized in the neuronal perikarya and delivered into synapses via two modes of axonal transport. While membrane-anchoring proteins are conveyed in fast axonal transport via motor-driven vesicles, cytosolic proteins travel in slow axonal transport via mechanisms that are poorly understood. We found that in cultured axons, populations of cytosolic proteins tagged to photoactivatable GFP (PAGFP) move with a slow motor-dependent anterograde bias distinct from both vesicular trafficking and diffusion of untagged PAGFP. The overall bias is likely generated by an intricate particle kinetics involving transient assembly and short-range vectorial spurts. In vivo biochemical studies reveal that cytosolic proteins are organized into higher order structures within axon-enriched fractions that are largely segregated from vesicles. Data-driven biophysical modeling best predicts a scenario where soluble molecules dynamically assemble into mobile supramolecular structures. We propose a model where cytosolic proteins are transported by dynamically assembling into multiprotein complexes that are directly/indirectly conveyed by motors.

A Combinatorial Semaphorin Code Instructs the Initial Steps of Sensory Circuit Assembly in the Drosophila CNS

Longitudinal axon fascicles within the Drosophila embryonic CNS provide connections between body segments and are required for coordinated neural signaling along the anterior-posterior axis. We show here that establishment of select CNS longitudinal tracts and formation of precise mechanosensory afferent innervation to the same CNS region are coordinately regulated by the secreted semaphorins Sema-2a and Sema-2b. Both Sema-2a and Sema-2b utilize the same neuronal receptor, plexin B (PlexB), but serve distinct guidance functions. Localized Sema-2b attraction promotes the initial assembly of a subset of CNS longitudinal projections and subsequent targeting of chordotonal sensory afferent axons to these same longitudinal connectives, whereas broader Sema-2a repulsion serves to prevent aberrant innervation. In the absence of Sema-2b or PlexB, chordotonal afferent connectivity within the CNS is severely disrupted, resulting in specific larval behavioral deficits. These results reveal that distinct semaphorin-mediated guidance functions converge at PlexB and are critical for functional neural circuit assembly.

Axons and myelinating glia: An intimate contact

The coordination of the vertebrate nervous system requires high velocity signal transmission between different brain areas. High speed nerve conduction is achieved in the myelinated fibers of both the central and the peripheral nervous system where the myelin sheath acts as an insulator of the axon. The interactions between the glial cell and the adjacent axon, namely axo-glial interactions, segregate the fiber in distinct molecular and functional domains that ensure the rapid propagation of action potentials. These domains are the node of Ranvier, the paranode, the juxtaparanode and the internode and are characterized by multiprotein complexes between voltage-gated ion channels, cell adhesion molecules, members of the Neurexin family and cytoskeletal proteins. In the present review, we outline recent evidence on the key players of axo-glial interactions, depicting their importance in myelinated fiber physiology and disease.

An enzymatic model of the growth hormone-releasing hormone oscillator incorporating neuronal synchronization

Models of growth hormone (GH) rhythmogenesis which we and others have presented suggest that the GH pulses in the circulation are generated by a GH-releasing hormone (GHRH) oscillator with a 1 h periodicity. Here we examine the possibility that this is an intrinsic neuronal rhythm resulting from enzymatic reactions occurring in the axon terminals. A "Baselator" feedback reaction sequence can generate an hourly chemical burst of a primer (presumably a low molecular weight peptide) regulating Ca 2+ -triggered exocytosis of GHRH-loaded vesicles. Accordingly we propose that the priming species is largely immobilized by binding within the terminals. Free unbound primer is able to diffuse and is alternately phosphorylated and dephosphorylated by a kinase and a phosphatase (or undergoes a similar pair of complementary reactions). Under appropriate conditions involving feedback control of one or other of the enzymes the levels of both unreacted and reacted free primer peak sharply at hourly intervals. It is self-evident that synchronization between the packed terminals of the GHRH neurons at the median eminence is necessary to generate highly ordered in vivo pulses of GH release. Gap junctions provide a means of interterminal communication for the primer. Simulations of clusters of 4 adjacent axon terminals in a linear array were performed to assess whether and when synchrony can occur. With gap junctions closed the axons were set to be 90° out of phase, i.e. their chemical bursts were separated by 15 min. Opening the gap junctions, assuming either that only the unphosphorylated species permeates, or that both species permeate, resulted in rapid overall synchronization. The oscillatory systems undergo mutual entrainment and all peaks appeared simultaneously at an intermediate hourly interval. This result was independent of the mode of chemical feedback, whether positive or negative. Closing the gap junctions led to a gradual, but not immediate, loss of synchrony.

Medullary neurons in the core white matter of the olfactory bulb: a new cell type

The structure of a new cell type, termed the medullary neuron (MN) because of its intimate association with the rostral migratory stream (RMS) in the bulbar core, is described in the adult rat olfactory bulb. The MN is a triangular or polygonal interneuron whose soma lies between the cellular clusters of the RMS or, less frequently, among the neuron progenitors therein. MNs are easily distinguished from adjacent cells by their large size and differentiated structure. Two MN subtypes have been categorized by the Golgi technique: spiny pyramidal neurons and aspiny neurons. Both MN subtypes bear a large dendritic field impinged upon by axons in the core bulbar white matter. A set of collaterals from the adjacent axons appears to terminate on the MN dendrites. The MN axon passes in close apposition to adjacent neuron progenitors in the RMS. MNs are immunoreactive with antisera raised against gamma-aminobutyric acid and glutamate decarboxylase 65/67. Electron-microscopic observations confirm that MNs correspond to fully differentiated, mature neurons. MNs seem to be highly conserved among macrosmatic species as they occur in Nissl-stained brain sections from mouse, guinea pig, and hedgehog. Although the functional role of MNs remains to be determined, we suggest that MNs represent a cellular interface between endogenous olfactory activity and the differentiation of new neurons generated during adulthood.

Chronically CNS-Injured Adult Sensory Neurons Gain Regenerative Competence upon a Lesion of Their Peripheral Axon

Several experimental manipulations result in axonal regeneration in the central nervous system (CNS) when applied before or at the time of injury but not when initiated after a delay, which would be clinically more relevant. As centrally injured neurons show signs of atrophy and degeneration, it raises the question whether chronically injured neurons are able to regenerate. To address this question, we used adult rodent primary sensory neurons that regenerate their central axon when their peripheral axon is cut (called conditioning) beforehand but not afterwards. We found that primary sensory neurons express regeneration-associated genes and efficiently regrow their axon in cell culture two months after a central lesion upon conditioning. Moreover, conditioning enables central axons to regenerate through a fresh lesion independent of a previous central lesion. Using in vivo imaging we demonstrated that conditioned neurons rapidly regrow their axons through a fresh central lesion. Finally, when single sensory axons were cut with a two-photon laser, they robustly regenerate within days after attaining growth competence through conditioning. We conclude that sensory neurons can acquire the intrinsic potential to regenerate their axons months after a CNS lesion, which they implement in the absence of traumatic tissue.

Computer simulation of cortical development

Event Abstract Back to Event Computer simulation of cortical development Sabina Pfister1*, A. Hauri1, F. Zubler1, R. Bauer1, A. M. Whatley1 and R. J. Douglas1 1 University of Zurich and ETH Zurich, Institut fur Neuroinformatik, Switzerland Simulation is a valuable tool for exploring self organization in neural-tissue development. We present our latest results in modeling corticogenesis using the simulator CX3D. An artificial genetic code is integrated into an initial progenitor cell, under the influence of which the progenitor undergoes cycles of symmetrical and asymmetrical division to form populations of distinct neuron precursors. The genetic code also governs the migration of the precursors to form a layered structure, and the expression of layer-specific dendritic and axonal arbors. We compare our results with measurements of reconstructed neurons from cat visual cortex and observed cell lineages in the cortex of embryonic mice. Moreover, by adding synaptic connections between adjacent axons and dendrites, we generate a neural network with connectivity analogous to that observed in the cortex. A description of this network can be exported to PCSIM to simulate the electrophysiology of the network. Conference: Neuroinformatics 2009, Pilsen, Czechia, 6 Sep - 8 Sep, 2009. Presentation Type: Poster Presentation Topic: Computational neuroscience Citation: Pfister S, Hauri A, Zubler F, Bauer R, Whatley AM and Douglas RJ (2019). Computer simulation of cortical development. Front. Neuroinform. Conference Abstract: Neuroinformatics 2009. doi: 10.3389/conf.neuro.11.2009.08.114 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 25 May 2009; Published Online: 09 May 2019. * Correspondence: Sabina Pfister, University of Zurich and ETH Zurich, Institut fur Neuroinformatik, Zurich, Switzerland, sabina@ini.ch Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Sabina Pfister A. Hauri F. Zubler R. Bauer A. M Whatley R. J Douglas Google Sabina Pfister A. Hauri F. Zubler R. Bauer A. M Whatley R. J Douglas Google Scholar Sabina Pfister A. Hauri F. Zubler R. Bauer A. M Whatley R. J Douglas PubMed Sabina Pfister A. Hauri F. Zubler R. Bauer A. M Whatley R. J Douglas Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Pathologic Characterization of a Murine Model of Human Enterovirus 71 Encephalomyelitis

We describe a model of Enterovirus 71 encephalomyelitis in 2-week-old mice that shares many features with the human central nervous system (CNS) disease. Mice were infected via oral and parenteral routes with a murine-adapted virus strain originally from a fatal human case. The mice succumbed to infection after 2 to 5 days. Vacuolated and normal-appearing CNS neurons showed viral RNA and antigens and virions by in situ hybridization, immunohistochemistry, and electron microscopy; inflammation was minimal. The most numerous infected neurons were in anterior horns, motor trigeminal nuclei, and brainstem reticular formation; fewer neurons in the red nucleus, lateral cerebellar nucleus, other cranial nerve nuclei, motor cortex, hypothalamus, and thalamus were infected. Other CNS regions, dorsal root, and autonomic ganglia were spared. Intramuscular-inoculated mice killed 24 to 36 hours postinfection had viral RNA and antigens in ipsilateral lumbar anterior horn cells and adjacent axons. Upper cord motor neurons, brainstem, and contralateral motor cortex neurons were infected from 48-72 hours. Viral RNA and antigens were abundant in skeletal muscle and adjacent tissues but not in other organs. The distinct, stereotypic viral distribution in this model suggests that the virus enters the CNS via peripheral motor nerves after skeletal muscle infection, and spread within the CNS involves motor and other neural pathways. This model may be useful for further studies on pathogenesis and for testing therapies.

Using nonlinear diffusion and mean shift to detect and connect cross-sections of axons in 3D optical microscopy images

The morphology of neuronal axons has been actively investigated by researchers to understand functionalities of neuronal networks, for example, in developmental neurology. Today's optical microscope and labeling techniques allow us to obtain high-resolution images about axons in three dimensions (3D), however, it remains challenging to segment and reconstruct the 3D morphology of axons. These include differentiating adjacent axons and detecting the axon branches. In this paper we present a method to track axons in 3D by identifying cross-sections of axons on 2D images and connecting the cross-sections over a series of 2D images to reconstruct the 3D morphology. The method can separate adjacent axons and detect the split and merge of axons. The method consists of three steps, modified nonlinear diffusion to remove noise and enhance edges in 2D, morphological operations to detect edges of the cross-sections of axons in 2D, and mean shift to track the cross-sections of axons in 3D. Performance of the method is demonstrated by processing real data acquired by confocal laser scanning microscopy.

Mechanisms of Pain and Itch Caused by Herpes Zoster (Shingles)

Study of humans with shingles or postherpetic neuralgia (PHN) is providing insights into pain mechanisms. Shingles pain is a combination of normal and neuropathic pain that reflects acute tissue and neural injury. PHN pain, which lasts after tissues have healed, is caused by persistent neural injuries. Spontaneous C-nociceptor activity has been documented in painful polyneuropathies and probably occurs in shingles as well, although there are no microneurographic studies of either shingles or PHN. It is uncertain if this persists in PHN since pathological examination of PHN-affected nerves and ganglia show chronic neuronal loss and quiescent scarring without inflammation. Skin-biopsy study has correlated the presence of PHN with the severity of persistent distal nociceptive axon loss, and autopsy has correlated pain persistence with segmental atrophy of the spinal cord dorsal horn, highlighting the importance of central responses to nerve injury. Pathological studies of tissues from patients with trigeminal neuralgia suggest that brief lancinating pains reflect ephaptic neurotransmission between adjacent denuded axons. The mechanisms of chronic spontaneous pain and mechanical allodynia remain uncertain despite considerable indirect evidence from animal models. Postherpetic itch is presumably caused by unprovoked firing of the peripheral and/or central neurons that mediate itch. If it occurs in neurons innervating skin left severely deafferented from shingles ("numb"), patients can give themselves painless injuries from scratching. Further human study, by electrophysiological recording, by structural and functional imaging, and by autopsy, should continue to provide much-needed insights. Many patients continue to have chronic pain and/or itch after shingles that is unrelieved by current treatments. Many will gladly volunteer for clinical studies, including autopsy, to try and improve understanding of these common and disabling conditions. Their prevalence makes highly powered studies feasible. Funding and organization are the current bottlenecks.

Astrocyte glycogen and brain energy metabolism

The brain contains glycogen but at low concentration compared with liver and muscle. In the adult brain, glycogen is found predominantly in astrocytes. Astrocyte glycogen content is modulated by a number of factors including some neurotransmitters and ambient glucose concentration. Compelling evidence indicates that astrocyte glycogen breaks down during hypoglycemia to lactate that is transferred to adjacent neurons or axons where it is used aerobically as fuel. In the case of CNS white matter, this source of energy can extend axon function for 20 min or longer. Likewise, during periods of intense neural activity when energy demand exceeds glucose supply, astrocyte glycogen is degraded to lactate, a portion of which is transferred to axons for fuel. Astrocyte glycogen, therefore, offers some protection against hypoglycemic neural injury and ensures that neurons and axons can maintain their function during very intense periods of activation. These emerging principles about the roles of astrocyte glycogen contradict the long held belief that this metabolic pool has little or no functional significance.

Second Harmonic and Sum Frequency Generation Imaging of Fibrous Astroglial Filaments in Ex Vivo Spinal Tissues

Sum frequency generation (SFG) and second harmonic generation (SHG) were observed from helical fibrils in spinal cord white matter isolated from guinea pigs. By combining SFG with coherent anti-Stokes Raman scattering microscopy, which allows visualization of myelinated axons, these fibers were found to be distributed near the surface of the spinal cord, between adjacent axons, and along the blood vessels. Using 20- μm-thick tissue slices, the ratio of forward to backward SHG signal from large bundles was found to be much larger than that from small single fibrils, indicating a phase-matching effect in coherent microscopy. Based on the intensity profiles across fibrils and the size dependence of forward and backward signal from the same fibril, we concluded that the main SHG signal directly originates from the fibrils, but not from surface SHG effects. Further polarization analysis of the SHG signal showed that the symmetry property of the fibril could be well described with a cylindrical model. Colocalization of the SHG signal with two-photon excitation fluorescence (TPEF) from the immunostaining of glial fibrillary acidic protein demonstrated that SHG arises from astroglial filaments. This assignment was further supported by colocalization of the SHG contrast with TPEF signals from astrocyte processes labeled by a Ca 2+ indicator and sulforhodamine 101. This work shows that a combination of three nonlinear optical imaging techniques—coherent anti-Stokes Raman scattering, TPEF, and SHG (SFG) microscopy—allows simultaneous visualization of different structures in a complex biological system.

Multiple sclerosis, brain radiotherapy, and risk of neurotoxicity: The Mayo Clinic experience

The aim of this study was a retrospective assessment of neurotoxicity in patients with multiple sclerosis (MS) receiving external beam radiotherapy (EBRT) to the brain. We studied 15 consecutively treated patients with MS who received brain EBRT. Neurologic toxicity was assessed with the Common Toxicity Criteria v.3.0. Median follow-up for the 5 living patients was 6.0 years (range, 3.3-27.4 years). No exacerbation of MS occurred in any patient during EBRT. Five patients had Grade 4 neurologic toxicity and 1 had possible Grade 5 toxicity. Kaplan-Meier estimated risk of neurotoxicity greater than Grade 4 at 5 years was 57% (95% confidence interval, 27%-82%). Toxicity occurred at 37.5 to 54.0 Gy at a median of 1.0 year (range, 0.2-4.3 years) after EBRT. Univariate analysis showed an association between opposed-field irradiation of the temporal lobes, central white matter, and brainstem and increased risk of neurotoxicity (p < 0.04). Three of 6 cases of toxicity occurred in patients treated before 1986. External beam radiotherapy of the brain in patients with MS may be associated with an increased risk of neurotoxicity compared with patients without demyelinating illnesses. However, this risk is associated with treatment techniques that may not be comparable to modern, conformal radiotherapy.

Point:Counterpoint: The parafacial respiratory group (pFRG)/pre-Bötzinger complex (preBötC) is the primary site of respiratory rhythm generation in the mammal

Point:Counterpoint: The parafacial respiratory group (pFRG)/pre-Bötzinger complex (preBötC) is the primary site of respiratory rhythm generation in the mammal

Netrin-1 Is Required for the Normal Development of Spinal Cord Oligodendrocytes

Successful CNS myelination is dependent on the correct localization of oligodendrocytes and their interactions with adjacent axons. In the spinal cord, oligodendrocyte precursors originate at the ventral midline and subsequently migrate to the white matter where they mature. In vitro studies suggest this dispersal is mediated by the guidance molecule netrin-1. Here, we show that in the spinal cord of netrin-1 mutant mice, oligodendrocyte precursors failed to disperse from the ventral midline as a consequence of a lack of polarization and directional migration. The lack of netrin-1 also resulted in an overall reduction of oligodendrocyte lineage cells that was independent of the failure of initial dispersal. Oligodendrocyte precursors injected into presumptive white matter underwent extensive radial migration and expansion in wild-type but not netrin-1 mutant hosts. These data indicate that netrin-1 is crucial for both the initial dispersal of spinal cord oligodendrocyte precursors and their subsequent development in the presumptive white matter.