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PubMed1998

In vitro studies of growth cone behavior support a role for fasciculation mediated by cell adhesion molecules in sensory axon guidance during development.

Axonal interactions, which are mediated by cell adhesion molecules (CAMs) as well as other types of membrane proteins, are important for sensory axon pathfinding in the developing chick hindlimb. We have previously shown that injection of antibodies that block the function of either G4/L1 or N-cadherin into the limb, starting when the first sensory axons reach the plexus, alters the segmental pattern of projections along cutaneous nerves. Specific removal of polysialic acid from NCAM using the enzyme endoneuraminidase N (Endo N) also resulted in significant changes in cutaneous projection patterns, while injection of antibodies against NCAM itself had no obvious effect (M. G. Honig and U. S. Rutishauser, 1996, Dev. Biol. 175, 325-337). To help understand the cellular basis for these findings, we developed a tissue culture system in which the axons from dorsal root ganglion explants grow within defined laminin lanes and examined whether the same treatments increased or decreased a growth cone's tendency to be closely associated with neighboring axons. After 2 days in culture, images of the cultures were recorded, antibodies or Endo N was added, and images of the same fields were recaptured an hour later. To quantify the results, growth cones located in defined regions of the laminin lanes were classified, before and after the perturbation, as "free" (i.e., growing primarily on the laminin substratum), "fasciculated" (i.e., growing tightly along other neurites), or "intermediate" (i.e., growing both on the laminin substratum and in contact with other neurites). We found that anti-G4/L1 and anti-N-cadherin, but not anti-NCAM, caused an increase in defasciculated growth cones, whereas Endo N resulted in an increase in fasciculated growth cones. These changes in fasciculation are consistent with the changes in cutaneous projections seen in our previous in ovo perturbations. The results from these tissue culture experiments thus provide strong support for the idea that one mechanism by which CAMs affect sensory axon pathfinding in vivo is by regulating the affinity of sensory growth cones for neighboring axons, which in turn can modulate the growth cone's ability to navigate through the surrounding environment.

Animals↗
PubMed1991

Substratum regulation of neurite fasciculation.

A new clonal nerve-like cell line from the rat eye is used to show that cell-substratum adhesion can modulate neurite fasciculation. When cells are grown on a substratum of intermediate adhesiveness their neurites adhere to each other and form fascicles. In contrast, cells grown on more adhesive surfaces spread and extend individual neurites. The direct relationship between the initial rates of cell-substratum adhesion and neurite fasciculation shows that the extent of axon fasciculation which occurs in vivo may be determined by the extracellular environment through which the axons are growing.

Animals↗
PubMed1994

Vicia villosa agglutinin inhibits the fasciculation of vomeronasal axons in fetal rat vomeronasal organ culture.

The vomeronasal organ of rat was cultured from embryonic 15-day littermates. During 4-8 days in vitro, vomeronasal axons originating from the explants of vomeronasal organ formed 2-3 large fascicles. When Vicia villosa agglutinin (VVA) was added to the culture medium, fasciculation of the vomeronasal axons was inhibited. The timing of addition and the duration of the presence of VVA were related to the inhibition of fasciculation of vomeronasal axons. Glycocojugates that bind with the VVA may therefore play an important role in the fasciculation of developing vomeronasal axons.

Animals↗
PubMed1992

Role of muscle fasciculations in the generation of myopathies in mammalian skeletal muscle.

The myotoxicity of pyridostigmine bromide was investigated on rat diaphragm nerve-muscle preparations in vitro. Within 2 h of exposure to pyridostigmine (2 microM), diaphragm muscles exhibited ultrastructural alterations characterized by swelling of subjunctional mitochondria and disorganization of contractile proteins. These alterations developed both in the absence and presence of electrical stimulation of the phrenic nerve, and were accompanied by continuous muscle fasciculations. Pretreatment by tetrodotoxin suppressed both the muscle fasciculations and the appearance of myopathies. These findings suggest that fasciculations may be an important contributing factor in the development of anti-cholinesterase-induced myopathies.

Acetylcholinesterase↗
PubMed1994

Genetic analysis of Fasciclin II in Drosophila: defasciculation, refasciculation, and altered fasciculation.

The Drosophila neural cell adhesion molecule Fasciclin II (Fas II) is expressed dynamically on a subset of embryonic CNS axons, many of which selectively fasciculate in the vMP2, MP1, and FN3 pathways. Here we show complementary fasII loss-of-function and gain-of-function phenotypes. Loss-of-function fasII mutations lead to the complete or partial defasciculation of all three pathways. Gain-of-function conditions, using a specific control element to direct increased levels of Fas II on the axons in these three pathways, rescue the loss-of-function phenotype. Moreover, the gain-of-function can alter fasciculation by abnormally fusing pathways together, in one case apparently by preventing normal defasciculation. These results define an in vivo function for Fas II as a neuronal recognition molecule that controls one mechanism of growth cone guidance-selective axon fasciculation--and genetically separates this function from other aspects of outgrowth and directional guidance.

Animals↗
PubMed1995

Mutations that affect the length, fasciculation, or ventral orientation of specific sensory axons in the Drosophila embryo.

In wild-type Drosophila embryos, five lateral chordotonal (lch) axons in each abdominal hemisegment originate from a midlaterally positioned cluster of neurons and grow, fasciculate, and orient ventrally as they connect with targets in the CNS. We have identified 22 recessive lethal mutations in 12 complementation groups, 8 of which are novel, that differentially affect lch axon growth, fasciculation, or ventral orientation. Mutations in 3 loci result in shorter, but fasciculated and ventrally directed axon bundles. Mutations in 4 complementation groups cause lch axon defasciculation. Mutations in 7 complementation groups cause some lch axon bundles to grow dorsally along a trajectory 180 degrees from normal.

Animals↗
PubMed2005

Chondroitin sulfate proteoglycan phosphacan associates with parallel fibers and modulates axonal extension and fasciculation of cerebellar granule cells.

Phosphacan is a nervous system-specific chondroitin sulfate proteoglycan and one of the major components of extracellular matrix in the brain. In the present study, we examined its spatiotemporal expression, ultrastructural localization, binding manner, and in vitro analysis on cell adhesion, axonal extension, and fasciculation in rat cerebellum. The present light microscopic immunohistochemistry showed that phosphacan immunoreactivity was localized mainly at the molecular layer in the cerebellum, but not at the external granular layer. Further double labeling immunohistochemical and immunoelectron microscopic studies revealed that phosphacan was localized around parallel fibers, but not at synapses. The binding of phosphacan to membrane and/or extracellular matrix partly required Ca2+ and was mediated through its core glycoprotein. Phosphacan inhibited adhesion and axonal extension of cerebellar granule cells in dissociated culture, while it promoted axonal fasciculation of their aggregated culture. These results indicate that phosphacan around parallel fibers may be the repulsive substratum for adhesion and extension of granule cells and promote the fasciculation of parallel fibers.

Animals↗
PubMed2004

Neural cell adhesion molecule L1 is required for fasciculation and routing of thalamocortical fibres and corticothalamic fibres.

To examine the role of neural cell adhesion molecule L1 in thalamocortical projections, we analysed L1 deficient (L1-/y) mice. Immunohistochemistry of pleiotrophin/HB-GAM, a marker for thalamocortical axons and axonal tracing experiments showed that thalamocortical axons were abnormally and highly fasciculated when they pass through the developing internal capsule. Within the cortex, however, their course was more diffuse. The corticofugal fibres immunoreactive for TAG-1 were also more strongly fasciculated and their number was decreased in L1-/y mice. Furthermore, no TAG-1-positive corticofugal axons reached the dorsal thalamus. These data suggest that L1 plays an important role in the fasciculation and routing of axons connecting between the thalamus and the cortex.

Animals↗
PubMed2005

Adjacent pioneer commissural interneuron growth cones switch from contact avoidance to axon fasciculation after midline crossing.

Commissural interneurons (CI) of the vertebrate spinal cord are guided ventrally toward the floor plate, but subsequently cross the midline and select a longitudinal fascicle at specific dorsal-ventral (D-V) positions. We examined at high resolution the detailed behaviors of individual pathfinding CI growth cones on the ipsilateral and contralateral sides of the spinal cord of living Xenopus embryos. We find that pre-crossing CI growth cones exhibit distinct pathfinding behaviors compared to post-crossing axons and that the behavioral switch occurs immediately upon crossing to the contralateral side. Groups of pioneer commissural axons typically extend simultaneously toward the ventral midline following discrete paths with separation between adjacent commissurals apparently maintained through contact inhibition. In contrast, shortly after crossing the midline, commissural axons turn longitudinally and begin to fasciculate with other crossed CIs. However, growth cones of crossed commissurals often select their final D-V longitudinal track through a series of rapid step-like dorsal adjustments that may be due to differential fasciculation with longitudinal axons. Together, our results suggest that guidance of commissural axons is controlled in part through interactions among CIs that switch rapidly from avoidance to fasciculation after midline crossing.

Animals↗
PubMed1998

Adhesion and signaling in axonal fasciculation.

Numerous in vitro assays and in vivo perturbation studies have led to a model of neural development in which selective fasciculation helps to define accurate axonal projections. Genetic analysis in vivo confirms the hypothesis that axonal fasciculation and defasciculation are controlled by adhesion mechanisms, but also suggests that, in many cases, adhesion and guidance are separable phenomena. In addition, receptors that control the level of tyrosine phosphorylation may play an important role in fasciculation, suggesting that complex intracellular pathways lie just beneath the surface.

Animals↗
PubMed1991

Phosphorylation-dependent regulation of axon fasciculation.

Axons often grow along other axons to produce bundles called fascicles, and a number of cell adhesion molecules (CAMs) found on axon surfaces contribute to this process. The surprising observation that Fab fragments against individual CAMs can completely block fascicle formation suggests that the different axon-associated CAMs are functionally linked. The present studies investigate whether such a linkage might reflect intracellular regulatory mechanisms. Results obtained with chicken retinal explants in culture indicate that fasciculation is highly sensitive to cytoplasmic protein phosphorylation by means of a mechanism that does not alter levels of CAM expression. Moreover, the potent effect of individual Fabs on fasciculation disappears with enhanced phosphorylation. These observations suggest that growing axons possess a general regulatory process for the multiple CAMs that participate in fasciculation.

Animals↗
PubMed1995

Fish E587 glycoprotein, a member of the L1 family of cell adhesion molecules, participates in axonal fasciculation and the age-related order of ganglion cell axons in the goldfish retina.

Axons derived from young ganglion cells in the periphery of the retinae of larval and adult goldfish are known to fasciculate with one another and their immediate forerunners, creating the typical age-related order in the retinotectal pathway. Young axons express the E587 antigen, a member of the L1 family of cell adhesion molecules. Repeated injections of Fab fragments from a polyclonal E587 antiserum (E587 Fabs) into the eye of 3.4 cm goldfish disrupted the orderly fascicle pattern of RGC axons in the retina which was preserved in controls. Instead of bundling tightly, RGC axons crossed one another, grew between fascicles and arrived at the optic disk in a broadened front. When added to RGC axons growing in vitro, E587 Fabs neutralized the preference of growth cones to elongate on lanes of E587 protein, caused defasciculation of axons which normally prefer to grow along each other when explanted on polylysine, and prevented clustering of E587 antigen at axon-axon contact sites. Monoclonal E587 antibody disturbed axonal fasciculation moderately but led to a 30% reduction in growth velocities when axons tracked other axons. Therefore we conclude that E587 antigen mediates axonal recognition, selective fasciculation and the creation of the age-related order in the fish retina.

Aging↗
PubMed1998

Neurite fasciculation mediated by complexes of axonin-1 and Ng cell adhesion molecule.

Neural cell adhesion molecules composed of immunoglobulin and fibronectin type III-like domains have been implicated in cell adhesion, neurite outgrowth, and fasciculation. Axonin-1 and Ng cell adhesion molecule (NgCAM), two molecules with predominantly axonal expression exhibit homophilic interactions across the extracellular space (axonin- 1/axonin-1 and NgCAM/NgCAM) and a heterophilic interaction (axonin-1-NgCAM) that occurs exclusively in the plane of the same membrane (cis-interaction). Using domain deletion mutants we localized the NgCAM homophilic binding in the Ig domains 1-4 whereas heterophilic binding to axonin-1 was localized in the Ig domains 2-4 and the third FnIII domain. The NgCAM-NgCAM interaction could be established simultaneously with the axonin-1-NgCAM interaction. In contrast, the axonin-1-NgCAM interaction excluded axonin-1/axonin-1 binding. These results and the examination of the coclustering of axonin-1 and NgCAM at cell contacts, suggest that intercellular contact is mediated by a symmetric axonin-12/NgCAM2 tetramer, in which homophilic NgCAM binding across the extracellular space occurs simultaneously with a cis-heterophilic interaction of axonin-1 and NgCAM. The enhanced neurite fasciculation after overexpression of NgCAM by adenoviral vectors indicates that NgCAM is the limiting component for the formation of the axonin-12/NgCAM2 complexes and, thus, neurite fasciculation in DRG neurons.

Animals↗
PubMed1999

Neurolin Ig domain 2 participates in retinal axon guidance and Ig domains 1 and 3 in fasciculation.

The optic disk-directed growth of retinal ganglion cell axons is markedly disturbed in the presence of polyclonal antineurolin antibodies, which mildly affect fasciculation (Ott, H., M. Bastmeyer, and C.A.O. Stuermer, 1998. J. Neurosci. 18:3363-3372). New monoclonal antibodies (mAbs) against goldfish neurolin, an immunoglobulin (Ig) superfamily cell adhesion/recognition molecule with five Ig domains, were generated to assign function (guidance versus fasciculation) to specific Ig domains. By their ability or failure to recognize Chinese hamster ovary cells expressing recombinant neurolin with deletions of defined Ig domains, mAbs were identified as being directed against Ig domains 1, 2, or 3, respectively. Repeated intraocular injections of a mAb against Ig domain 2 disturb the disk-directed growth: axons grow in aberrant routes and fail to reach the optic disk, but remain fasciculated. mAbs against Ig domains 1 and 3 disturb the formation of tight fascicles. mAb against Ig domain 2 significantly increases the incidence of growth cone departure from the disk-oriented fascicle track, while mAbs against Ig domains 1 and 3 do not. This was demonstrated by time-lapse videorecording of labeled growth cones. Thus, Ig domain 2 of neurolin is apparently essential for growth cone guidance towards the disk, presumably by being part of a receptor (or complex) for an axon guidance component.

Activated-Leukocyte Cell Adhesion Molecule↗
PubMed1980

Effects of fasciculation on the outgrowth of neurites from spinal ganglia in culture.

This report describes the influence of neurite fasciculation on two aspects of nerve growth from chick spinal ganglia in vitro: the inhibition of outgrowth by high concentrations of nerve growth factor (NGF) and the preferential growth of neurites toward a capillary tube containing NGF. These studies involved a comparison of cultures of single cells, cell aggregates, and intact ganglia and the use of antibodies against the nerve cell adhesion molecule (CAM) to perturb fasciculation under a variety of conditions. The inhibition of outgrowth, which was observed with ganglia and aggregates but not with single cells, was correlated with a thickening of neurite fascicles. In accord with this observation, anti-CAM, which diminishes fasciculation by inhibiting side-to-side interactions between individual neurites, also partially reversed the inhibition of neurite outgrowth at high NGF concentrations. On the basis of these and other studies, we consider the possibility that neurite bundling causes an increase in the elastic tension of a fascicle without a compensatory increase in its adhesion to substratum. It is proposed that this imbalance could inhibit neurites from growing out from a ganglion and even result in retraction of preexisting outgrowth. In the analysis of NGF-directed growth, it was found that a capillary source of NGF produced a steep but transient NGF gradient that subsided before most neurites had emerged from the ganglion. Nevertheless, the presence of a single NGF capillary caused a dramatic and persistent asymmetry in the outgrowth of neurites from ganglia or cell aggregates. In contrast, processes of individual cells did not appear to orient themselves toward the capillary. The most revealing finding was that anti-CAM antibodies caused a decrease in the asymmetry of neurite outgrowth. These results suggest that side-to-side interactions among neurites can influence the guidance of nerve bundles by sustaining and amplifying an initial directional signal.

Animals↗
PubMed1991

Changes in excitability of human motor axons underlying post-ischaemic fasciculations: evidence for two stable states.

1. We have investigated the origin of post-ischaemic ectopic discharges in human nerve by recording changes in electrical excitability following periods of ischaemia (15-20 min) sufficient to induce spontaneous motor fasciculations. The ulnar nerve was stimulated beneath a pressure cuff on the upper arm, and compound motor action potentials recorded from abductor digiti minimi. 2. On releasing the cuff after 15 min of ischaemia, thresholds to short current pulses increased in two distinct phases: a slow phase followed by a rapid rise to a peak threshold. The rapid rise was too fast to track (i.e. 100% threshold increase in less than 4 s), and was sometimes followed after 30-40 s by an equally rapid fall. Small polarizing currents affected the timing of the rapid threshold increase, as if it was occurring at a particular membrane potential. 3. By recording complete stimulus-response curves every few seconds, we found that the rapid threshold changes were associated with a bimodal distribution of thresholds. Most fibres were found in either a high-threshold or low-threshold state, and these two states converged over a period of about 10 min. 4. Spontaneous motor fasciculations were only recorded after the rapid rise in threshold and when the fibres existed in two threshold states. The spontaneous activity was not responsible for inducing the two states, since they could also be recorded in its absence. 5. A computer model of a human motor axon node and internode was constructed, incorporating channel types demonstrated in other axons, and channel densities adjusted to match the responses of human axons to depolarizing and hyperpolarizing current pulses. An increase in extracellular potassium concentration produced a region of negative slope conductance in the current-voltage relationship of the model, and the appearance of two stable states with enhanced activity of the electrogenic sodium pump. 6. Transitions between the two stable states of the model could account qualitatively for the rapid threshold changes recorded from post-ischaemic axons. In the model, spontaneous action potentials occurred following some transitions from the high potential state to the low potential state. We suggest that post-ischaemic motor fasciculations in man also involve transitions between two equilibrium states, occurring in axons with high extracellular potassium and high electrogenic pump activity.

Action Potentials↗
PubMed1976

Detection of somatic muscle fasciculation on electrocardiograms.

Small discrete spikes appearing on the electrocardiogram (ECG) of a man with a pacemaker turned out to be fasciculation potentials picked up from leg muscles. To find out how common these spikes were all routine ECGs made in one month were reviewed. Spike potentials were found in six patients, and in each case they originated from somatic musculature. Spikes could nearly always be detected on ECGs that were recorded subsequently in patients known to have lower motor neurone lesions that produced fasciculation. Thus the presence of these fasciculation spikes may suggest underlying neuromuscular disease; this possibility should be recognised by those who record ECGs so that the spikes are not suppressed by overuse of the filter.

Arm↗
PubMed2005

[Cramp-fasciculation syndrome].

The cramp-fasciculation syndrome is a rare clinical entity in comparison with the frequency of cramps and isolated fasciculations in the general population. It is recognized as a benign syndrome without weakness and atrophy, however a few reports suggest that it may precede the occurrence of a motor neuron disease. Most often, the cramp-fasciculation syndrome is idiopathic and may be a component of a hyperexcitable peripheral nerve syndrome including other activities such as myokymia and neuromyotonia where antibodies to voltage-gated potassium channels (VGKCs) appear to be one of the effector mechanisms. The most complete form of this hyperexcitable peripheral nerve syndrome is Isaacs' syndrome. The central nervous system is also concerned with anti-VGKC antibodies found in Morvan's disease and limbic encephalitis which is often a paraneoplastic condition. These findings extend the spectrum of the anti-VGKC syndrome that may be associated with other auto-immune diseases, chiefly myasthenia gravis with thymoma. Carbamazepine and phenytoin cause reduction of the clinical and electrophysiological signs of the nerve hyperexcitability, and plasmapheresis and (or) immunosuppressors are useful when an auto-immune origin is considered.

Humans↗