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PubMed1998

The diffusion of molecules in axonal plasma membranes: the sites of insertion of new membrane molecules and their distribution along the axon surface.

The neuronal cell surface consists of two domains, the somatodendritic and axonal plasma membranes. Each domain serves different functions, and has a different complement of membrane molecules. Since membrane molecules are able to diffuse in the plane of the plasma membrane lipid bilayer, with diffusion coefficients ranging from 10-8 cm 2 s-1 for lipids to 10-10 cm 2 s-1 for proteins, mechanisms must exist to prevent as intermixing of membrane molecules from each domain by diffusion. Presented here is a theoretical analysis of the distribution of axonal molecules in both growing and non-growing axons based on two models for the insertion of these molecules into the axonal membrane, namely insertion exclusively at the distal end of the axon, or insertion with equal probability all along the axon. In all cases, assuming that the molecules have a finite half-life in the axonal membrane, compositional differences between the axonal and somatodendritic membranes can be obtained that are similar to those observed in other polarized cells, even in the absence of a physical barrier to prevent the intermixing of membrane molecules. Moreover, our analyses demonstrate that the diffusion of membrane molecules in the plane of the axonal lipid bilayer is a sufficiently slow process to preclude the possibility that membrane molecules are inserted into axonal membranes at a site remote from their final location, and then move to their final locations for diffusion. Thus, in long axons, for membrane molecules that are localized all along the length of the axon, mechanisms must exist for their insertion in the axonal membrane at sites all along the axon, and not just at the distal end.

Animals↗

PubMed1981

4S RNA is transported axonally in normal and regenerating axons of the sciatic nerves of rats.

Experiments were designed to determine if following injection of [3H]uridine into the lumbar spinal cord of the rat, [3H]RNA could be demonstrated within axons of the sciatic nerve, and if 4S RNA is the predominant RNA species present in these axons. In one experiment the left sciatic nerve of a rat was crushed. Two days later 170 microCi of [3H]uridine was injected into the vicinity of the lumbar ventral horn cells. Ten days after injection, rats were sacrificed and sciatic nerves were prepared for autoradiography. Photomicrographs were taken of labeled areas of intact and regenerating nerves and grains were counted over Schwann cells, myelin, axons and other unspecified areas. In both intact and regenerating sciatic nerves more than 20% of the silver grains were associated with motor axons and approximately 40% were found over cytoplasm of Schwann cells surrounding these axons. These data indicate an intra-axonal localization of RNA in sciatic nerve axons, as well as an active transfer of RNA precursors from axons to their surrounding Schwann cels. In separate studies, the left sciatic nerve was crushed and 10 days later [3H]uridine was bilaterally injected intraspinally into 6 rats. Four control rats were sacrificed at 14 or 20 days after injection. In the remaining 2 rats the sciatic nerve was cut 14 days after injection and the distal part of the nerve was allowed to degenerate for 6 days before sacrificing the rat. Thus, the distal portion of the nerve contained Schwann cells labeled by axonal transport but lacked intact axons. RNA was isolated from experimental and control nerve segments by hot phenol extraction and ethanol precipitation. RNA species (28S, 18S and 4S) were separated by polyacrylamide gel electrophoresis and radioactivity was measured in a liquid scintillation counter. Control groups had RNA profiles similar to those already described, with greater than 30% of the radioactivity present as 4S RNA. The proximal portions of nerve taken from the group in which nerves were cut, had a similar amount of radioactivity present as 4S RNA. However, in the distal segments of these nerves (in which the axons had degenerated thus creating an 'axon-less' nerve) the amount of radioactivity in the 4S peak decreased to approximately 15% of the total RNA, suggesting that 4S RNA is the predominant if not the only RNA present in these axons. These results strongly indicate that both intact and regenerating sciatic nerves of rats selectively transport 4S RNA along their motor axons.

Animals↗

PubMed2004

Glia engulf degenerating axons during developmental axon pruning.

Developmental axon pruning is widely used in constructing the nervous system. Accordingly, diverse mechanisms are likely employed for various forms of axon pruning. In the Drosophila mushroom bodies (MB), gamma neurons initially extend axon branches into both the dorsal and medial MB axon lobes in larvae. Through a well-orchestrated set of developmental events during metamorphosis, axon branches to both lobes degenerate prior to the formation of adult connections. Here, we analyze ultrastructural changes underlying axon pruning by using a genetically encoded electron microscopic (EM) marker to selectively label gamma neurons. By inhibiting axon pruning in combination with the use of this EM marker, we demonstrate a causal link between observed cellular events and axon pruning. These events include changes in axon ultrastructure, synaptic degeneration, and engulfment of degenerating axon fragments by glia for their subsequent breakdown via the endosomal-lysosomal pathway. Interestingly, glia selectively invade MB axon lobes at the onset of metamorphosis; this increase in cell number is independent of axon fragmentation. Our study reveals a key role for glia in the removal of axon fragments during developmental axon pruning.

Animals↗

PubMed2005

Central and peripheral axon branches from one neuron are guided differentially by Semaphorin3D and transient axonal glycoprotein-1.

For multiple axons from one neuron to extend in different directions to unique targets, the growth cones of each axon must have distinct responses to guidance cues. However, the mechanisms by which separate axon branches are guided along different pathways are mainly unknown. Zebrafish Rohon-Beard (R-B) sensory neurons extend central axon branches in the spinal cord and peripheral axons to the epidermis. To investigate the differential guidance mechanisms of the central versus peripheral R-B axon branches, we used live-growth cone imaging in vivo combined with manipulation of individual guidance molecules. We show that a semaphorin expressed at the dorsal spinal cord midline, Semaphorin3D (Sema3D), may act to repel the peripheral axons out of the spinal cord. Sema3D knock-down reduces the number of peripheral axons. Remarkably, Sema3D ectopic expression repels and induces branching of peripheral axons in vivo but has no effect on central axons from the same neurons. Conversely, central axons require a growth-promoting molecule, transient axonal glycoprotein-1 (TAG-1), to advance, whereas peripheral axons do not. After TAG-1 knock-down, central growth cones display extensive protrusive activity but make little forward advance. TAG-1 knock-down has no effect on the motility or advance of peripheral growth cones. These experiments show how Sema3D and TAG-1 regulate the motility and behavior of growth cones extending in their natural in vivo environment and demonstrate that two different axon branches from one neuron respond differently to guidance cues in vivo.

Amino Acids↗

PubMed1991

Stages of growth of hamster retinofugal axons: implications for developing axonal pathways with multiple targets.

Neurons in many regions of the CNS (e.g., cortical areas, thalamic nuclei) are heterogeneous with regard to their afferent and efferent connections. Using the hamster retinofugal system as a model, we investigated the mechanisms by which such connectional heterogeneity arises during ontogeny. Retinal ganglion cell axons were labeled with 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (Dil) in paraformaldehyde-fixed tissue. The fluorescent label was photoconverted to a diaminobenzidine reaction product. The morphology of the axons, including their trajectories, branching patterns, and growth cones, was studied at the level of the dorsal lateral geniculate nucleus (LGd) from embryonic day 14 to adulthood. In adult hamsters, axons of retinal ganglion cells (RGCs) are spatially segregated at the level of the lateral geniculate nucleus into a superficial optic tract, situated just beneath the pia, and an internal optic tract consisting of fascicles running parallel to the pia within the geniculate. All retinofugal axons project to the midbrain, but only superficial optic tract axons emit collaterals to the LGd. During development, axons in both divisions of the optic tract emit collaterals to the LGd, but by postnatal day 15, collaterals of internal optic tract axons are virtually entirely eliminated, whereas those of superficial optic tract axons have elaborated terminal arbors. Thus, the heterogeneity among different classes of RGCs with respect to their efferent connections emerges by the selective stabilization, by each class, of a unique subset of connections from an initially widespread set shared by all classes. Thalamic collaterals of RGC axons emerge along established axon trunks, not by bifurcation of the growing tip. This occurs after the axons have grown past the thalamus and, presumably, entered their targets in the midbrain. Growth cones at the tips of elongating axon trunks are larger in size and have a more "complex" morphology compared to the growth cones on collaterals. Axons of RGCs develop in 3 morphologically distinct growth states. First, they elongate to their most distant targets in the midbrain. Then, they simultaneously emit unbranched or poorly branched collaterals to multiple targets. Finally, they elaborate terminal arbors in their definitive targets and eliminate their other collaterals. This developmental strategy may be paradigmatic for the formation of long CNS pathways with multiple targets. Furthermore, these data document, at the single-axon level, the steps in the elaboration and withdrawal of transient neuronal projections.

Animals↗

PubMed1989

Selective metabolic labeling of axonal proteins: an in vitro approach for the identification and characterization of axonal proteins and their role in health and disease.

In order to identify and characterize the molecular building blocks underlying axonal functions and axon-glia interactions, we have developed an approach to the identification of molecules that are subjected to axonal transport. A compartmental cell culture system that offers separate access to cell somas and axons was used. This system allows identification and selective investigation of proteins of axons even when they are located in a variable cellular environment. A number of axonal and axonally secreted proteins specific for neuronal subpopulations were identified. Furthermore, we have shown that co-cultured cells from the peripheral nervous system and the central nervous system modulate the synthesis of a few axonal proteins of dorsal root ganglions neurons differentially. Axonal and axonally secreted proteins selected by this approach are now investigated in greater detail by cell biological, biochemical, and recombinant DNA technologies to obtain insight into the molecular details of the processes acting in the implementation and regulation of axonal functions. The presented approach is generally applicable to neuronal subpopulation that can be grown in culture, and represents an excellent tool for the investigation of various aspects of axonal functions and axon-glia or axon-neuron interactions on health and disease.

Animals↗

PubMed1985

Variability in the terminations of GABAergic chandelier cell axons on initial segments of pyramidal cell axons in the monkey sensory-motor cortex.

Chandelier cell axons were studied in the sensory-motor cortex of adult monkeys. The axonal fields of Golgi-impregnated chandelier cells in layer II in motor cortex are flattened sagittally. The vertical terminal portions of the axons varied both in length and in the numbers converging to form terminations of greater or lesser complexity. Golgi-impregnated plexuses were embedded in plastic and resectioned serially at 2.5-3.0 micrograms. A single axonal field could have as many as 400 terminal rows. All lie 3-13 micrograms beneath pyramidal cell somata. These terminations are not randomly distributed but instead, form clusters. Further resectioning the plastic sections for electron microscopy revealed that all the terminations are on the initial axon segments of pyramidal cells and all form symmetric synaptic contacts. In immunocytochemical material stained for glutamic acid decarboxylase (GAD), the enzyme involved in the synthesis of GABA, GAD-positive boutons were found to form symmetric synaptic contacts with a variety of postsynaptic elements including the axon hillocks and axon initial segments of pyramidal cells. Serial reconstructions from electron micrographs revealed GAD-positive terminals synapsing with the axon initial segment of pyramidal cells joined by cytoplasmic bridges and forming vertically oriented rows identical to those of chandelier cell terminals identified positively in the resectioned Golgi material. The GAD-positive terminals forming initial segment synapses were never continuous with GAD-positive terminals forming axo hillock synapses. The latter probably arise from basket cell axons. Initial segments of pyramidal cell axons in layers II and III were contacted by more GAD-positive terminals than the initial segments of pyramidal cell axons in layer V. The largest pyramidal cells in layer III received the most synapses. Many larger pyramidal cells, identified as callosally projecting cells by the retrograde transport of horseradish peroxidase (HRP), were shown in serial electron micrographs to possess large numbers of initial segment synapses, comparable to those seen in the immunocytochemical material. Serial reconstructions of pyramidal cell axons from axon hillock to the first myelin internode in resectioned Golgi, immunocytochemical and HRP material showed that the number of synapses varied from 2 to 52 for layers II and III and from 2 to 26 for layer V. The number of synapses on the axon hillocks varied from zero to 12. The variability in these terminations may be an important factor in the shaping of the functional properties of the pyramidal cells.

Animals↗

PubMed2004

Slow component of axonal transport is impaired in the proximal axon of transgenic mice with a G93A mutant SOD1 gene.

The purpose of this study was to determine whether slow axonal transport of neurofilaments (NFs) is impaired in the spinal cord of G93A Cu/Zn superoxide dismutase (SOD1) mutant transgenic mice expressing a relatively low mutant protein (gene copy 10) and, if so, how the impairment occurs in this animal model. Transgenic mice were killed at the ages of 24, 28 and 32 weeks, and the cervical and lumbar spinal cords were examined under an electron microscope. Age-matched non-transgenic wild-type mice served as controls. At 24 weeks (early presymptomatic stage), anterior horn cells were well preserved. The earliest morphological changes were mild vacuolar changes in the neuronal processes, particularly in proximal axons. At 28 weeks (late presymptomatic stage), mild neuronal loss of anterior horn neurons was observed. Vacuolar changes were more prominent in the proximal axons, including swollen axons (spheroids) and neuropils of the anterior horns. Vacuoles in the axons were frequently large enough to occupy almost the entire axonal caliber. The anterior roots were degenerative, showing vacuolar changes and myelin ovoids. Lewy body-like inclusions (LIs) consisting of filaments thicker than NFs (about 1.5 times larger in diameter) were frequently demonstrated in the neuronal processes including swollen axons (spheroids) and occasionally in the somata. At 32 weeks (symptomatic stage), the anterior horns showed a moderate to severe neuronal loss accompanied by prominent astrogliosis. Cord-like swollen axons consisting of accumulated NFs and many neurofilamentous accumulations were frequently observed in the anterior horn. Vacuolar changes were less prominent or disappeared in the neuropils of the anterior horns and the anterior roots, whereas LIs were frequently demonstrated within the neuronal processes including the cord-like swollen axons. In the anterior roots, degenerative changes such as marked fiber loss and frequent myelin ovoids were remarkable. No accumulation of NFs or mitochondrial vacuolation was detected in somata or proximal dendrites at any stage. These findings suggest that the slow component of axonal transport in the proximal axons is impaired at an early stage in this transgenic mouse model, and that the impairment is probably caused by a mechanical impediment of NFs, or by the accumulation of NFs in the proximal axon, as a result of the obstruction of the axonal flow that initially occurs by vacuolar changes, and is later exacerbated by accumulation of LIs.

Alanine↗

PubMed2000

Neurofilaments are transported rapidly but intermittently in axons: implications for slow axonal transport.

Slow axonal transport conveys cytoskeletal proteins from cell body to axon tip. This transport provides the axon with the architectural elements that are required to generate and maintain its elongate shape and also generates forces within the axon that are necessary for axon growth and navigation. The mechanisms of cytoskeletal transport in axons are unknown. One hypothesis states that cytoskeletal proteins are transported within the axon as polymers. We tested this hypothesis by visualizing individual cytoskeletal polymers in living axons and determining whether they undergo vectorial movement. We focused on neurofilaments in axons of cultured sympathetic neurons because individual neurofilaments in these axons can be visualized by optical microscopy. Cultured sympathetic neurons were infected with recombinant adenovirus containing a construct encoding a fusion protein combining green fluorescent protein (GFP) with the heavy neurofilament protein subunit (NFH). The chimeric GFP-NFH coassembled with endogenous neurofilaments. Time lapse imaging revealed that individual GFP-NFH-labeled neurofilaments undergo vigorous vectorial transport in the axon in both anterograde and retrograde directions but with a strong anterograde bias. NF transport in both directions exhibited a broad spectrum of rates with averages of approximately 0.6-0.7 microm/sec. However, movement was intermittent, with individual neurofilaments pausing during their transit within the axon. Some NFs either moved or paused for the most of the time they were observed, whereas others were intermediate in behavior. On average, neurofilaments spend at most 20% of the time moving and rest of the time paused. These results establish that the slow axonal transport machinery conveys neurofilaments.

Adrenergic Fibers↗

PubMed1983

Correlation of axonal regeneration and slow component B in two branches of a single axon.

We investigated the relationship between slow axonal transport and axonal regeneration in the rat dorsal root ganglion (DRG) cell. The DRG cell sends out a single axon which bifurcates within the ganglion; one axon proceeds centrally into the spinal cord and the other proceeds peripherally. The rate of axonal regeneration is approximately 2 times faster for the peripheral processes (4.6 +/- 0.9 mm/day) than for the central processes (2.1 +/- 0.5 mm/day). The peripheral and central processes regenerate through dissimilar environments (sciatic nerve and dorsal root, respectively); thus, environmental factors may account for the differences in regeneration rates. We tested this possibility by measuring the regeneration of motoneuron axons within the ventral root (histologically similar to the dorsal root). The motoneuron regeneration rate within the ventral root is similar to the motoneuron regeneration rate within the sciatic nerve, suggesting that factors within the DRG cell produce the differences in regeneration rate. Slow axonal transport is classified into two distinct components: slow component a (SCa), corresponding to the microtubule/neurofilament network of the axonal cytoskeleton, and slow component b (SCb), corresponding to the microfilament complex/axoplasmic matrix. The transport rate of SCa and SCb in the peripheral sensory axons is approximately 2 times faster than their counterparts in the central sensory axons. SCa moves at 1.0 to 3.0 mm/day in the peripheral processes and 0.5 to 1.0 mm/day in the central processes; SCb moves at 3.5 to 6.5 mm/day in the peripheral processes and 2.0 to 3.5 mm/day in the central processes. In each branch of the DRG cell, the rate of axonal regeneration is similar to the rate of SCb transport. These results support the hypothesis that SCb is a rate-limiting factor in axonal regeneration because of its role in providing the cytoskeletal elements which are directly involved in the motility of the growth cone and elongation of the axon.

Animals↗

PubMed1983

Axonal patterns and topography of short-axon neurons in visual areas 17, 18, and 19 of the cat.

In a Golgi study of short-axon cells in areas 17, 18, and 19 of the adult cat, 21 main axonal arborization patterns are distinguished and related to laminar position and dendritic morphology. Multipolar neurons exclusive to layer 2/3 exhibit the greatest diversity of axons: These may be arranged in a local tuft, a single descending stem with recurrent collaterals, a columnar descending plexus, horsetaillike bundles, a dense intralaminar plexus, or a varicose local arbor. Multipolar cells of layers 2--5 may have local basket or chandelier axons or a neurogliform axonal plexus, and axons in layer 4 may branch into a columnar basket plexus. Two types of multipolar cells are described in layers 5 and 6. Also, neurons with a bitufted dendritic tree have different axonal patterns: cone-shaped axons, arcade axons, profuse ascending plexuses, and columnar or diffuse ascending and descending arbors. The axons of bitufted cells in layer 6 ascend or form a local tuft. Finally, giant bitufted cells with local axons, bitufted or multipolar cells with horizontal axons, and bipolar cells are described. The neuronal types established on the basis of their axonal arbor are compared to previous classifications of cortical neurons. The location of neurons thus classified has been recorded and evaluated. Most cells show no topographical specificity and occur indistinctly in the three visual areas, while two types are exclusive to area 17. Horsetail neurons accumulate at the 17/18 and 18/19 borders. Multipolar cells of layer 2/3 with a dense intralaminar plexus and chandelier cells are concentrated in the region where the central visual field is represented.

Animals↗

PubMed1993

Axon hillocks and initial segments in spinal trigeminal nucleus with emphasis on synapses including axo-axo-axonic contacts.

As a part of a continuing study of the feline spinal trigeminal nucleus, the fine structure and synaptic arrangements on the axon hillock and axon initial segment of neurons in this region are described here. Transmission electron microscopy has been used to characterize qualitatively the axon hillock and initial segment and associated synapses in pars interpolaris. Axon hillocks and initial segments are easily identified in continuity with somata or as isolated profiles in the neuropil, and they receive synaptic contacts: these we regard as axo-axonic. The presynaptic terminals contain either mainly round or mainly flattened synaptic vesicles and have Type I (asymmetric) or Type II (symmetric) thickenings respectively at their contacts with the axon hillock or initial segment. I report here also the unusual arrangement of three separate axons in a serial synaptic complex. Some of the round vesicle Type I contacts onto the axon hillock-initial segment region also receive Type II contacts from one or more flattened vesicle terminals, thus forming an axo-axo-axonic complex. These flattened vesicle terminals lack the usual features of a presynaptic dendrite. It has been shown that in this nucleus some round vesicle terminals, especially those postsynaptic to flattened vesicle terminals, are primary afferents from the periphery. Therefore the round vesicle terminal presynaptic to the axon hillock-initial segment region, some of which are included in the axo-axo-axonic complex may also be a primary afferent directly contacting the spike generator area of the relay neuron and under presynaptic control of a flattened vesicle synapse. The latter may possibly be an intrinsic contact. This strategic situation of round vesicle terminals and the axo-axo-axonic complex at the axon hillock or initial segment has major implications relevant to the overall output of these neurons.

Animals↗

PubMed1997

Role of lipoproteins in the delivery of lipids to axons during axonal regeneration.

Nerve fiber elongation involves the input of lipids to the growing axons. Since cell bodies are often a great distance from the regenerating tips, alternative sources of lipids have been proposed. We previously demonstrated that axonal synthesis of phosphatidylcholine is required for axonal growth (Posse de Chaves, E., Vance, D. E., Campenot, R. B. and Vance, J. E. (1995) J. Cell Biol. 128, 913-918; Posse de Chaves, E., Vance, D. E., Campenot, R. B. and Vance, J. E. (1995) Biochem. J. 312, 411-417). In contrast, cholesterol is not made in axons. We now show that when compartmented cultures of rat sympathetic neurons are incubated with pravastatin, in the absence of exogenously supplied lipids, cholesterol synthesis is inhibited and axonal growth is impaired. The addition of cholesterol to the axons or cell bodies of neurons treated with this inhibitor restores normal axonal elongation. Similarly, a supply of cholesterol via lipoproteins restores normal axonal growth. In contrast, lipoproteins do not provide axons with sufficient phosphatidylcholine for normal elongation when axonal phosphatidylcholine synthesis is inhibited. Thus, our studies support the idea that during axonal regeneration lipoproteins can be taken up by axons from the microenvironment and supply sufficient cholesterol, but not phosphatidylcholine, for growth. We also show that neither apoE nor apoA-I within the lipoproteins is essential for axonal growth.

Animals↗

PubMed2002

Coupling of calcium homeostasis to axonal sodium in axons of mouse optic nerve.

Axonal populations in neonatal and mature optic nerves were selectively stained with calcium dyes for analysis of calcium homeostasis and its possible coupling to axonal Na. Repetitive nerve stimulation causes a rise in axonal [Ca(2+)](i) the posttetanus recovery of which is impeded by increasing the number of action potentials in the tetanus. This effect is augmented in 4-aminopyridine (4-AP; 1 mM), which dramatically increases the calcium and presumably sodium load during the tetanus. Increasing axonal [Na](i) with the Na-ionophore monensin (4-50 microM) and ouabain (30 microM) retards posttetanus calcium decline, suggesting that efficient calcium clearance depends on a low level of axonal [Na](i). Posttetanus calcium clearance is not affected by K-mediated depolarization. To further examine coupling between axonal [Na](i) and [Ca(2+)](i), the resting axonal [Ca(2+)](i) was monitored as axonal [Na(+)](i) was elevated with ouabain, veratridine, and monensin. In all cases, elevation of axonal [Na(+)](i) evokes a calcium influx into axons. This influx is unrelated to activation of calcium channels but is consistent with calcium influx via reversal of the Na/Ca exchanger expected as a consequence of axonal [Na(+)](i) elevation. In conclusion, this study demonstrates that calcium homeostasis in the axons of the optic nerve is strongly coupled to axonal [Na(+)](i) in a manner consistent with the Na/Ca exchanger playing a major role in extruding calcium following nerve activity.

4-Aminopyridine↗

PubMed2003

Axon fasciculation and differences in midline kinetics between pioneer and follower axons within commissural fascicles.

Early neuronal scaffold development studies suggest that initial neurons and their axons serve as guides for later neurons and their processes. Although this arrangement might aid axon navigation, the specific consequence(s) of such interactions are unknown in vivo. We follow forebrain commissure formation in living zebrafish embryos using timelapse fluorescence microscopy to examine quantitatively commissural axon kinetics at the midline: a place where axon interactions might be important. Although it is commonly accepted that commissural axons slow down at the midline, our data show this is only true for leader axons. Follower axons do not show this behavior. However, when the leading axon is ablated, follower axons change their midline kinetics and behave as leaders. Similarly, contralateral leader axons change their midline kinetics when they grow along the opposite leading axon across the midline. These data suggest a simple model where the level of growth cone exposure to midline cues and presence of other axons as a substrate shape the midline kinetics of commissural axons.

Animals↗

PubMed2004

An axon scaffold induced by retinal axons directs glia to destinations in the Drosophila optic lobe.

In the developing Drosophila visual system, glia migrate into stereotyped positions within the photoreceptor axon target fields and provide positional information for photoreceptor axon guidance. Glial migration conversely depends on photoreceptor axons, as glia precursors stall in their progenitor zones when retinal innervation is eliminated. Our results support the view that this requirement for retinal innervation reflects a role of photoreceptor axons in the establishment of an axonal scaffold that guides glial cell migration. Optic lobe cortical axons extend from dorsal and ventral positions towards incoming photoreceptor axons and establish at least four separate pathways that direct glia to proper destinations in the optic lobe neuropiles. Photoreceptor axons induce the outgrowth of these scaffold axons. Most glia do not migrate when the scaffold axons are missing. Moreover, glia follow the aberrant pathways of scaffold axons that project aberrantly, as occurs in the mutant dachsous. The local absence of glia is accompanied by extensive apoptosis of optic lobe cortical neurons. These observations reveal a mechanism for coordinating photoreceptor axon arrival in the brain with the distribution of glia to multiple target destinations, where they are required for axon guidance and neuronal survival.

Animals↗

PubMed2001

A functional role for intra-axonal protein synthesis during axonal regeneration from adult sensory neurons.

Although intradendritic protein synthesis has been documented in adult neurons, the question of whether axons actively synthesize proteins remains controversial. Adult sensory neurons that are conditioned by axonal crush can rapidly extend processes in vitro by regulating the translation of existing mRNAs (Twiss et al., 2000). These regenerating processes contain axonal but not dendritic proteins. Here we show that these axonal processes of adult sensory neurons cultured after conditioning injury contain ribosomal proteins, translational initiation factors, and rRNA. Pure preparations of regenerating axons separated from the DRG cell bodies can actively synthesize proteins in vitro and contain ribosome-bound beta-actin and neurofilament mRNAs. Blocking protein synthesis in these regenerating sensory axons causes a rapid retraction of their growth cones when communication with the cell body is blocked by axotomy or colchicine treatment. These findings indicate that axons of adult mammalian neurons can synthesize proteins and suggest that, under some circumstances, intra-axonal translation contributes to structural integrity of the growth cone in regenerating axons. By immunofluorescence, translation factors, ribosomal proteins, and rRNA were also detected in motor axons of ventral spinal roots analyzed after 7 d in vivo after a peripheral axonal crush injury. Thus, adult motor neurons are also likely capable of intra-axonal protein synthesis in vivo after axonal injury.

Actins↗

PubMed1995

The first retinal axon growth in the mouse optic chiasm: axon patterning and the cellular environment.

The retinofugal pathway is a useful model for axon guidance because fibers from each eye project to targets on both sides of the brain. Studies using static and real time analyses in mice at E15-17 demonstrated that uncrossed axons from ventrotemporal retina diverge from crossed axons in the optic chiasm, where specialized resident cells may direct divergence. Other studies, however, suggest that pioneering uncrossed retinal axons derive from a different retinal region, take a different course, and enter the ipsilateral optic tract independent of fiber-fiber interactions. We examine these differences by dye-labeling the earliest optic axons and immunocytochemically identifying cells in their path. The first optic axons arising from dorsocentral retina, enter the diencephalon at E12.5. All axons initially grow caudally, lateral to a radial glial palisade. In contrast to later growing axons, early uncrossed axons enter the ipsilateral optic tract directly. Crossed axons enter the glial palisade and course medially, then anteriorly, in a pathway corresponding to the border of an early neuronal population that expresses SSEA-1, CD44, and beta-tubulin. Axon patterning occurs independent of fiber-fiber interactions from both eyes, as the first uncrossed axons enter the optic tract before crossed ones from opposite eye. These analysis, in conjunction with our previous studies during the principal period of retinal axon growth in the diencephalon, suggest that the adult visual projection arises from age-dependent variations in the types and relative contribution of cues along the path through the emerging optic chiasm.

Animals↗