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PubMed1989

The effects of 12-O-tetradecanoylphorbol-13-acetate (TPA) on axonal elongation and fasciculation.

Ultrastructural examination of neurons treated with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) confirmed our previous finding that TPA promoted neurite differentiation. At the low concentration of 16 nM TPA, the outgrowth of long neurites was correlated with the increased appearance of membrane-filled varicosities and filopodial extensions along the axons. In contrast, treatment with high concentrations of TPA (160 nM) produced dense outgrowths which were shorter in length and organized as thick fascicles. Increased neurite fasciculation appeared to result from the enhanced side-to-side interactions of neighboring neurites by a neural cell adhesion molecule. Axons within these fascicles were retracted and appeared congested with cytoskeletal and membranous components. Treatment with the antibody to the neural cell adhesion molecule defasciculated the thick outgrowths and permitted further axonal elongation.

Animals↗
PubMed2005

Odorant receptor proteins in olfactory axons and in cells of the cribriform mesenchyme may contribute to fasciculation and sorting of nerve fibers.

Odorant receptors (ORs) have been shown to be present not only in the chemosensory cilia of the olfactory sensory neurons, but also in their axon terminals. This observation has emphasized the notion that the receptor protein may contribute to the precise receptor-specific targeting of olfactory axons in the olfactory bulb. This concept implies a particularly important role for the axonal receptor protein during the onset and early phase of the wiring process during development. In the present study, we have demonstrated, by means of specific antibodies, that, as early as mouse embryonic day E12, the OR protein can be visualized in outgrowing axonal processes of the olfactory epithelium and in cells located in the cribriform mesenchyme. On their trajectory from the olfactory epithelium through the cribriform mesenchyme toward the forebrain, axons with strong OR immunoreactivity have only been seen in the dorsal part of the mesenchyme where they traverse the region of OR-positive cells. Upon visualization by specific antibodies, these cells have been revealed to have long protrusions extending along the surface of nerve fascicles. They are often located at bifurcations where two small axon fascicles merge to form a stronger bundle. Within this region, fascicles coalesce forming a coherent nerve. Moreover, within the now compact nerve bundle, axons visualized by the OR-specific antibody are no longer distributed evenly but are segregated from other axonal populations within the nerve. These findings suggest that OR proteins in the membrane of axonal processes and of cells in the cribriform mesenchyme are involved in crucial processes such as fasciculation and the sorting of outgrowing axons, both of which are fundamental for the initiation and establishment of the precise wiring of the olfactory system during early development.

Animals↗
PubMed1997

Roles of a neuronal cell-surface molecule, neuropilin, in nerve fiber fasciculation and guidance.

Neuropilin is a cell-surface glycoprotein that was first identified in Xenopus tadpole nervous tissues and then in chicken and mouse. The primary structure of neuropilin is highly conserved among these vertebrate species. The extracellular part of the molecule is composed of three domains referred to as a1/a2, b1/b2, and c, each of which is expected to be involved in molecular and/or cellular interactions. Neuropilin can mediate cell adhesion by heterophilic molecular interaction. In all vertebrate species examined, the neuropilin protein is restricted to axons of particular neuron classes, and at stages when axon growth is active. The gain and loss of function of neuropilin in developing mouse embryos causes defasciculation and incorrect sprouting of nerve fibers. These findings suggest that neuropilin serves in a variety of neuronal cell interactions by binding to a variety of molecules, and that it plays essential roles in nerve fiber fasciculation and guidance.

Animals↗
PubMed1991

Glycosylphosphatidylinositol anchored recognition molecules that function in axonal fasciculation, growth and guidance in the nervous system.

A large number of glycoproteins in the central nervous system are attached to the cell membrane via covalent linkage to glycosylphosphatidylinositol (GPI). Many of them, including the drosophila fasciclin 1 as well as the mammalian glycoproteins Thy-1, TAG1, N-CAM and F11,F3, contactin are members of the immunoglobulin gene superfamily. These and other GPI-linked molecules have been implicated in key developmental events including selective axonal fasciculation and highly specific growth to and innervation of target tissues. In model systems fasciclin 1, TAG1 and N-CAM have been shown to be capable of mediating cell-cell adhesion via a homophilic binding mechanism confirming their operational classification as cell adhesion molecules (CAMs). However, of these molecules, only N-CAM has been shown to mediate a complex response (neurite outgrowth) via a homophilic binding mechanism. Whether the other molecules in this family mediate biological responses by binding to themselves and/or other molecules remains to be determined. Studies on N-CAM provide an ideal model system for understanding the function of GPI anchors since alternative splicing of the NCAM gene generates both lipid-linked and transmembrane N-CAM isoforms. Recent studies have shown that neurons can recognise and respond (by increased neurite outgrowth) to both lipid-linked and transmembrane N-CAM isoforms expressed on the surface of non-neuronal cells following transfection with appropriate cDNAs. The major determinant of neuronal responsiveness was the level of N-CAM expression rather than the isoform type. Neurite outgrowth in response to transfected N-CAM is mediated by transmembrane N-CAM isoforms expressed by neurons and this involves the activation of classical second messenger pathways in the neurons. One possibility is that GPI anchors are utilised when a cell has simply to provide recognition or positional information to a second cell whereas transmembrane molecules might be required for cells that actively respond to such information. The hypothesis is compatible with all the known information on N-CAM expression and function and may be extended to other adhesive events.

Amino Acid Sequence↗
PubMed2006

Fasciculation and elongation protein zeta-1 (FEZ1) participates in the polarization of hippocampal neuron by controlling the mitochondrial motility.

The fasciculation and elongation protein zeta-1 (FEZ1), a mammalian orthologue of Caenorhabditis elegans UNC-76 protein, is a 45-kDa protein with four coiled-coiled domains and efficiently promotes the neurite elongation in the rat phaeochromocytoma PC12 cells. UNC-76 proteins of C. elegans and Drosophila have been genetically demonstrated to be involved in the axonal guidance. We here show that FEZ1 RNA interference (RNAi) represses the formation of axon in rat embryo hippocampal neurons. An anterograde mitochondrial movement is also retarded in neurites of the RNAi-treated hippocampal neurons. Moreover, the size of mitochondria is considerably elongated by the RNAi treatment. The transport of mitochondria from soma to axon or dendrites is essential for the neuronal differentiation. Therefore, our results strongly suggest that FEZ1 participates in the establishment of neuronal polarity by controlling the mitochondrial motility along axon.

Adaptor Proteins, Signal Transducing↗
PubMed2005

A novel function for cadherin-11 in the regulation of motor axon elongation and fasciculation.

We previously observed that cadherin-11, a type II cadherin, is expressed in growing motor and sensory axons in the mouse embryo. Here, we assessed its functional involvement in the regulation of axon elongation and fasciculation by evaluating the activity of a specific cadherin-11 homophilic ligand, cad11-Fc (cadherin-11 extracellular region fused to Fc fragment of IgG), on the length and organization of motor axons outgrowing from embryonic ventral spinal cord explants. Cad11-Fc substrate enhanced axon growth and prevented interactions occurring between growing axons, providing evidences for a role of cadherin-11 in the control of growth cone progression. Comparison of cadherin-11 with N-cadherin, a type I cadherin concomitantly expressed by motor axons, revealed similarities in their functional properties, including the ability to reorganize the actin cytoskeleton through interactions with catenins, but differences in their axon growth-promoting activity, arguing for subtle differences in their contributions to peripheral nerve elongation.

Animals↗
PubMed2002

Extracellular serine protease neuropsin (KLK8) modulates neurite outgrowth and fasciculation of mouse hippocampal neurons in culture.

A serine protease neuropsin expressed in the hippocampus of adult brain has been implicated in synaptic plasticity. We report here that endogenous neuropsin was localized extracellularly in neuronal cell bodies and their neurites in mouse hippocampal cultures. Furthermore, we found that, in cultured mouse hippocampal neurons, recombinant neuropsin enhanced neurite projection from soma after 14 h of culture and neuronal aggregation with neurite fascicles at 48 h. This suggests that neuropsin is involved in neurite outgrowth and fasciculation during the development of the nervous system.

Aging↗
PubMed1997

Neuronal migrations and axon fasciculation are disrupted in ina-1 integrin mutants.

Integrins are heterodimeric cell surface receptors implicated in cell adhesion and signaling. Our analysis of C. elegans ina-1 alpha integrin mutants provides the first genetic evidence that migrating neurons require integrins. Mosaic analysis and expression studies show that ina-1 acts autonomously in cells to promote their migrations. Although axons generally extend to their normal targets in ina-1 mutants, bundling of axons into fascicles is defective, defining a previously unrecognized role for integrins. In addition to these neuronal phenotypes, ina-1 mutants also display many morphogenetic defects. Finally, we show that the C. elegans INA-1 alpha integrin subunit associates with the PAT-3beta subunit in vivo, suggesting that these proteins function together in cell migration, axon fasciculation, and morphogenesis.

Animals↗
PubMed1988

Botulinum toxin injections in the treatment of blepharospasm, hemifacial spasm, and eyelid fasciculations.

Seventy-six patients with blepharospasm (mean age 56.9 years) received 248 injection treatments with botulinum A exotoxin (mean 3.1 treatments per patient): 87.0% of treatments led to total relief of spasms for a mean interval of 14.1 weeks. The average duration of response remained fairly constant over the first six injection series, although patients with the most severe spasms had shorter intervals than patients with less severe symptoms. Twenty patients with hemifacial spasm (mean age 56.9 years) received 44 treatments (mean 1.9 treatments per patient): In 93.1% of cases there was total relief of periocular and perioral spasms, with a mean interval of 17.4 weeks. The average duration of response for the third series of treatments was much shorter than the mean durations for the first two treatments. Side effects were always transient and included ptosis (23.3%), dry eyes (18.1%), tearing (5.5%), and strabismus (1.4%). No patient had a systemic reaction to the drug. Chronic benign eyelid fasciculations were also successfully treated in 3 patients with single treatments.

Adult↗
PubMedDate not supplied

The optic tract in embryonic hamsters: fasciculation, defasciculation, and other rearrangements of retinal axons.

The early development of the optic tract in hamsters was studied by labeling retinal axons with Dil applied to the eye, and then examining the labeled axons in flatmount preparations of the rostral brain stem. This technique permits a panoramic view of the entire retinal projection, from the chiasm to the caudal end of the superior colliculus. In the E11 embryo, retinal axons have reached the chiasm. They defasciculate as they emerge from the nerve, prior to reaching the ventral midline of the diencephalon, then converge again as they pass over to the opposite side. At the midline, many axonal trajectories crisscross, implying some shuffling of relative positions. Retinal axons are tightly bundled within the optic tract. Upon reaching the ventral border of the lateral geniculate body (LGB), they splay out over the nucleus, revealing a wavefront of pioneer axons individually distributed across the rostro-caudal extent of the LGB. Later-emerging retinal axons course over the surface of the thalamus in waves; subsequent waves of axons interdigitate between the lead fibers without fasciculating along them. Past the LGB, the axons undergo a second change in relative positions as the ribbon of fibers swerves caudally, prior to entering the superior colliculus. Retinal axons are tipped with growth cones of varying morphologies. No strong correlation is evident between the structural complexity of the growth cone and its position within the tract. In the majority of cases, ipsilaterally and contralaterally directed axons follow a similar developmental course along the optic tract, without any indication of a temporal lag in the ipsilateral projection as claimed in earlier reports. Understanding the changes in spatial distribution of embryonic retinal axons as they navigate along the optic tract provides a further step towards elucidating how point-to-point projections form in developing sensory systems.

Animals↗
PubMed2001

Neurotrimin expression during cerebellar development suggests roles in axon fasciculation and synaptogenesis.

We investigated the temporal expression of the neural cell adhesion molecule, neurotrimin, in the rat cerebellum and the brainstem from birth to adulthood using immunoreactive labeling. A wave of expression accompanied the development of projection pathways extending from brainstem nuclei (pons/inferior olive) through the cerebellar peduncles into the arbor vitae and disappeared with myelination by P14. Immuno-EM revealed expression of neurotrimin on the surface of unmyelinated axons but not on astrocytes or oligodendroglia. With the development of the molecular and internal granular layers, intense labeling occurred on the surface of parallel fiber bundles, granule cells and mossy fibers. With synaptogenesis, each excitatory junction was labeled by the immunoreaction. By P21, neurotrimin reactivity decreased on the surfaces of neuronal somata, dendrites and axons but remained at excitatory synaptic contact sites in both the molecular and granular layers. The spatial-temporal expression pattern of neurotrimin suggests that this adhesion molecule plays a role in axonal fasciculation of specific cerebellar systems and may also be involved in the formation of excitatory synapses and their stabilization into adulthood.

Afferent Pathways↗
PubMed2002

NBR1 interacts with fasciculation and elongation protein zeta-1 (FEZ1) and calcium and integrin binding protein (CIB) and shows developmentally restricted expression in the neural tube.

NBR1 (named as next to BRCA1) was originally cloned as a candidate gene for the ovarian cancer antigen CA125, using expression cloning with the anti-CA125 Ig, OC125. NBR1 has been of interest due to its position close to BRCA1, although no involvement in breast or ovarian cancer has been demonstrated. Recently, the antigen CA125 has been cloned, and identified as a new mucin, MUC16, entirely different from NBR1. The function of NBR1 remains unknown. To investigate its function, a yeast two-hybrid study was performed to identify interacting protein partners that may reflect a biological role for this protein. Here, we show that NBR1 interacts with two proteins; fasciculation and elongation protein zeta-1 (FEZ1), a PKCzeta interacting protein, and calcium and integrin binding protein (CIB), which is associated with polo-like kinases Fnk/Snk and the Alzheimer's disease presenilin 2 protein. Co-transfection of FEZ1 and NBR1 showed overlapping localization in the cytoplasm, whereas coexpression of NBR1 and CIB resulted in a shift of CIB protein expression from the nucleus to the perinuclear compartment. FEZ1 is highly expressed in the brain and in situ hybridization analysis of Nbr1 showed that its expression is also regulated in the murine brain during development. These data suggest that NBR1 may function, through interaction with CIB and FEZ1 in cell signalling pathways, with a developmentally restricted expression suggesting a possible role in neural development.

Adaptor Proteins, Signal Transducing↗
PubMed1987

Membrane glycoproteins involved in neurite fasciculation.

Lectin affinity chromatography combined with mAb production was used to identify chick neural cell surface molecules related to L1 antigen, a mouse neural glycoprotein implicated in cell-cell adhesion (Rathjen, F. G., and M. Schachner, 1984, EMBO (Eur. Mol. Biol. Organ.) J., 3:1-10). A glycoprotein, G4 antigen, isolated by mAb G4 from adult chick brain is described which comprises a major 135-kD component, a minor doublet at 190 kD, and diffusely migrating bands at 80 and 65 kD in SDS PAGE. This molecule is structurally related to mouse L1 antigen according to NH2-terminal amino acid sequence (50% identity) as well as the behavior of its components in two-dimensional IEF/SDS PAGE gels. A second chicken glycoprotein, F11 antigen, was isolated from adult chick brain using mAb F11. This protein has also a major 135-kD component and minor components at 170 kD and 120 kD. Both immunotransfer analysis with polyclonal antibodies to mAb G4 and to mAb F11 isolate and the behavior on IEF/SDS PAGE gels indicates that the major 135-kD component of F11 antigen is distinct from G4 antigen components. However, the 135-kD component of F11 antigen shares with G4 antigen and the neural cell adhesion molecule (NCAM) the HNK-1/L2 carbohydrate epitope. In immunofluorescence studies, G4 and F11 antigenic sites were found to be associated mainly with the surface of process-bearing cells, particularly in fiber-rich regions of embryonic brain. Although Fab fragments of polyclonal antibodies to mAbs G4 or F11 immunoaffinity isolate only weakly inhibit the Ca2+-independent aggregation of neural cells, they strongly inhibit fasciculation of retinal axons. Together these studies extend the evidence that bundling of axons reflects the combined effects of a group of distinct cell surface glycoproteins.

Amino Acid Sequence↗
PubMed1989

A homologue of the axonally secreted protein axonin-1 is an integral membrane protein of nerve fiber tracts involved in neurite fasciculation.

Axonin-1 is a glycoprotein that is released from axons of cultured neurons (Stoeckli, E. T., P. F. Lemkin, T. B. Kuhn, M. A. Ruegg, M. Heller, and P. Sonderegger. 1989. Eur. J. Biochem. 180:249-258). It has recently been purified from the ocular vitreous fluid of the chicken embryo (Ruegg, M. A., E. T. Stoeckli, T. B. Kuhn, M. Heller, R. Zuellig, and P. Sonderegger. 1989. EMBO (Eur. Mol. Biol. Organ.) J. 8:55-63). Immunohistochemistry localized axonin-1 prevalently in developing nerve fiber tracts. The presence of anti-axonin-1 Fab fragments during axon growth in vitro resulted in antibody binding to the axonal surfaces and in a marked perturbation of the fasciculation pattern. Hence, a fraction of axonin-1 is associated with axonal membranes and, by operational criteria, qualifies as a cell adhesion molecule. The major proportion of membrane-associated axonin-1 co-solubilized with the integral membrane proteins. By physico-chemical, immunological, and protein-chemical criteria, the integral membrane form was found to be highly similar to soluble axonin-1. In common with a number of other cell adhesion molecules, both soluble and membrane-bound axonin-1 express the L2/HNK-1 and the L3 epitopes. Radioactive pulse-chase and double-labeling experiments revealed that the released form was not derived from the membrane-bound form by shedding from the membrane surface, but directly secreted from an intracellular pool. Due to its high degree of similarity to the membrane-associated form and the presence of the L2/HNK-1 and L3 epitopes, reported to be ligands in adhesive cell interactions, adhesive properties are postulated for secreted axonin-1. As a soluble adhesive protein, it may function as a regulator of cell adhesion around its most likely site of secretion, the growth cone.

Animals↗
PubMed1990

Neuron-specific membrane glycoproteins promoting neurite fasciculation in Aplysia californica.

We have generated a library of mouse monoclonal antibodies against membrane proteins of the nervous system of the marine snail Aplysia californica. Two of these antibodies, 4E8 and 3D9, recognize a group of membrane glycoproteins with molecular masses of 100-150 kD. We have called these proteins ap100, from the molecular mass of the most abundant species. Based on Western blots, these proteins appear to be specific for the nervous system. They are enriched in the neuropil of central nervous system ganglia, and are present on the surface of neurites and growth cones of neurons in culture. They are not expressed on the surface of nonneuronal cells. Staining of living cells with fluorescently labeled mAb demonstrates that the epitope(s) are on the outside of the cell. The antibodies against the proteins defasciculate growing axons and alter the morphology of growth cones, but affect much less adhesion between neuritic shafts. In addition, the level of expression of these molecules appears to correlate with the degree of fasciculation of neurites. These observations suggest that the ap100 proteins are cell adhesion molecules that play a role in axon growth in the nervous system of Aplysia. The fact that they are enriched in the neuropil and possibly in varicosities suggest that they may also be relevant for the structure of mature synapses.

Animals↗
PubMed1996

Intracellular signaling is changed after clustering of the neural cell adhesion molecules axonin-1 and NgCAM during neurite fasciculation.

Neural cell adhesion molecules of the immunoglobulin/fibronectin type III family on axons have been implicated in promotion of neurite outgrowth, fasciculation, and the mediation of specific cell adhesion. The present study demonstrates that two of these molecules on dorsal root ganglion neurons are associated with distinct protein kinases, axonin-1 with the src-related nonreceptor tyrosine kinase fyn and NgCAM with a casein kinase II-related activity and a serine/ threonine kinase related to S6 kinase. When neurites grew without contacts involving axonin-1 and NgCAM, strong fyn kinase activity was associated with axonin-1, whereas the NgCAM-associated kinase activities were low. Clustering of axonin-1 with NgCAM induced by the formation of cell-cell contacts correlated with a reduction of the axonin-1-associated fyn activity and an increased phosphorylation of NgCAM by the associated casein kinase II-related activity. Thus, axonin-1 and NgCAM trigger distinctive intracellular signals during in vitro differentiation depending on their state of association.

Animals↗