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PubMed2005

Role of cyclin-dependent kinase 5 and its activator P35 in local axon and growth cone stabilization.

Axons elongate and perform steering reactions with their growth cones constantly undergoing local collapse and stabilization. Our previous studies have shown that a type-1 phosphorylated form of microtubule-associated protein 1B, recognized by monoclonal antibody 1E11 (mab1E11), is present in stable regions and absent from unstable regions of turning growth cones of retinal ganglion cells. In contrast, the total population of microtubule-associated protein 1B is present in the entire growth cone. Here we demonstrate that inhibition of cyclin-dependent kinase 5 (Cdk5) results in loss of mab1E11 binding whereas inhibition of glycogen synthase kinase 3 has no such effect, revealing that mab1E11 recognizes a Cdk5 phosphorylation site on type-1 phosphorylated form of microtubule-associated protein 1B. We moreover show that kinase Cdk5 as well as its activator P35 is present in retinal ganglion cells in the early developing chick embryo retina and enriched in their extending axons. Cdk5 and P35 are concentrated in the youngest, distal axon region and the growth cone as also seen for Cdk5-phosphorylated type-1 phosphorylated form of microtubule-associated protein 1B. Inhibition of Cdk5 by antibodies or inhibitor Roscovitine results in growth cone collapse and axon retraction and prevents substantial axon outgrowth. In contrast, glycogen synthase kinase 3 inhibition causes only a transient axon retraction which is soon recovered and allows for axon formation. In growth cones induced to turn at substrate borders, where stable and instable parts of the growth cone are clearly defined, Cdk5 is present in the entire growth cone. P35, in contrast, is restricted to the stable parts of the growth cone, which do not collapse but instead transform into new distal axon. The local presence of Cdk5-phosphorylated type-1 phosphorylated form of microtubule-associated protein 1B in stabilized growth cone areas can be therefore attributed to the local activation of Cdk5 by P35 in these regions. Together our data demonstrate a crucial role of Cdk5 and its activator P35 in elongation and maintenance of axons as well as for stability and steering of their growth cones.

Animals↗
PubMed2006

A role for neurotrophin-3 in targeting developing cholinergic axon projections to cerebral cortex.

This study examined the relationship between expression of neurotrophin-3 (NT-3) and the ingrowth of cholinergic axonal projections in cerebral cortex. Patterns of expression of NT-3 (defined by beta-galactosidase reporter expression in heterozygous offspring of transgenic NT-3(lacZneo/+) mice) revealed that limbic cortical regions (including frontal, cingulate, and insular cortex, as well as the dentate gyrus) express NT-3 and that these cortical regions receive early and relatively dense cholinergic axons (stained for acetylcholinesterase, AChE). Using the dentate gyrus as a model system, studies revealed that expression of the NT-3 reporter parallels, and precedes by approximately 2 days, the ingrowth of AChE positive cholinergic axons. Studies of forebrain organotypic slice cultures demonstrate that basal forebrain-derived cholinergic axons extend into cortical regions in a pattern that mimics the pattern of expression of the NT-3 reporter. Similarly, chimeric co-cultures, combining wild type septum with a slice of hippocampus from heterozygous NT-3(lacZneo/+) mice, demonstrate that cholinergic axons grow into regions of the dentate gyrus that express the NT-3 reporter. Hemisphere slice cultures made from NT-3 knockout mice reveal cholinergic axonal growth into cortex, but these axons do not form the regional pattern characteristic of slice cultures made from wild type or heterozygous NT-3(lacZneo/+) mice. Further, chimeric co-cultures made using slices of wild type septum combined with slices of hippocampus from NT-3 knockout mice demonstrate robust cholinergic axonal growth into the hippocampus, but the cholinergic axons do not form the characteristic preterminal pattern associated with the dentate gyrus. Slice cultures from limbic cortical tissue from the NT-3 null mice do not display exaggerated levels of cell death. In aggregate, these data support the hypothesis that expression of NT-3 by cortical neurons serves to attract basal forebrain cholinergic projections to their target cells in cerebral cortex.

Acetylcholinesterase↗
PubMed2004

gamma-Diketone neuropathy: axon atrophy and the role of cytoskeletal protein adduction.

Multifocal giant neurofilamentous axonal swellings and secondary distal degeneration have been historically considered the hallmark features of gamma-diketone neuropathy. Accordingly, research conducted over the past 25 years has been directed toward discerning mechanisms of axonal swelling. However, this neuropathological convention has been challenged by recent observations that swollen axons were an exclusive product of long-term 2.5-hexanedione (HD) intoxication at lower daily dose-rates (e.g., 175 mg/kg/day); that is, higher HD dose-rates (e.g., 400 mg/kg/day) produced neurological deficits in the absence of axonal swellings. The observation that neurological toxicity can be expressed without axonal swelling suggests that this lesion is not an important pathophysiological event. Instead, several research groups have now shown that axon atrophy is prevalent in nervous tissues of laboratory animals intoxicated over a wide range of HD dose-rates. The well-documented nerve conduction defects associated with axon atrophy, in conjunction with the temporal correspondence between this lesion and the onset of neurological deficits, strongly suggest that atrophy has pathophysiological significance. In this commentary, we present evidence that supports a pathognomonic role for axon atrophy in gamma-diketone neuropathy and suggests that the functional consequences of this lesion mediate the corresponding neurological toxicity. Previous research has demonstrated that HD interacts with proteins via formation of pyrrole adducts. We therefore discuss the possibility that this chemical process is essential to the mechanism of atrophy. Evidence presented in this review suggests that "distal axonopathy" is an inaccurate classification and future nosological schemes should be based on the apparent primacy of axon atrophy.

Animals↗
PubMed2004

Ectoderm removal prevents cutaneous nerve formation and perturbs sensory axon growth in the chick hindlimb.

Target tissues are thought to provide important cues for growing axons, yet there is little direct evidence that they are essential for axonal pathfinding. Here we examined whether target ectoderm is necessary for the formation of cutaneous nerves, and for the normal growth and guidance of cutaneous axons as they first enter the limb plexus. To do this, we removed a patch of ectoderm from the chick hindlimb at various times during early axon outgrowth. We find there is a critical period when cutaneous nerve formation requires target ectoderm. When the ectoderm is absent during this time, axons progress into the limb more slowly and, although a few sensory axons occasionally diverge a short distance from the plexus, they do not form a discrete nerve that travels to the skin. A few days later, when the nerve pattern is mature, axons normally destined for the 'deprived' cutaneous nerve are not segregated appropriately within the plexus. Some cutaneous axons are instead misdirected along an inappropriate cutaneous nerve, while others have seemingly failed to reach their correct target, or a suitable alternative, and died. These results demonstrate that the target ectoderm is necessary for normal sensory axon growth and guidance in the hindlimb.

Animals↗
PubMed2006

Characterization of loss-of-function and gain-of-function Eph receptor tyrosine kinase signaling in C. elegans axon targeting and cell migration.

To understand how our brains function, it is necessary to know how neurons position themselves and target their axons and dendrites to their correct locations. Several evolutionarily conserved axon guidance molecules have been shown to help navigate axons to their correct target site. The Caenorhabditis elegans Eph receptor tyrosine kinase (RTK), VAB-1, has roles in early neuroblast and epidermal cell movements, but its roles in axon guidance are not well understood. Here, we report that mutations that disrupt the VAB-1 Eph receptor tyrosine kinase cause incompletely penetrant defects in axonal targeting and neuronal cell body positioning. The predominant axonal defect in vab-1 mutant animals was an overextension axon phenotype. Interestingly, constitutively active VAB-1 tyrosine kinase signaling caused a lack of axon outgrowth or an early termination phenotype, opposite to the loss-of-function phenotype. The combination of loss-of-function and gain-of-function analyses suggests that the VAB-1 Eph RTK is required for targeting or limiting axons and neuronal cells to specific regions, perhaps by transducing a repellent or stop cue.

Animals↗
PubMed2006

EphB2 regulates axonal growth at the midline in the developing auditory brainstem.

Eph receptors play important roles in axon guidance at the midline. In the auditory system, growth of axons across the midline is an important determinant of auditory function. The avian cochlear nucleus, n. magnocellularis (NM), makes bilateral projections to its target, n. laminaris (NL). We examined the time course of NM axon growth toward the midline, the expression of Eph proteins at the midline during this growth, and the effects of Eph receptor misexpression on axonal growth across the midline. We found that NM axons reach the midline at E4. At this age, EphB receptors are expressed at the ventral floor plate. Expression extends dorsally to the ventricular zone beginning at E5. NM axons thus grow across the midline at a time when EphB receptor expression levels are low. Overexpression of EphB2 at E2 resulted in misrouted axons that deflected away from transfected midline cells. This effect was observed when midline cells were transfected but not when NM cells alone were transfected, suggesting that EphB2 acts non-cell autonomously and through reverse signaling. These data suggest an inhibitory role for midline Eph receptors, in which low levels permit axon growth and subsequently high levels prohibit growth after axons have crossed the midline.

Animals↗
PubMed2006

Slits contribute to the guidance of retinal ganglion cell axons in the mammalian optic tract.

RGC axons extend in the optic tracts in a manner that correlates with the expression in the hypothalamus and epithalamus of a soluble factor inhibitory to RGC axon outgrowth. Additionally, although the RGC axons extend adjacent to the telencephalon, they do not normally grow into this tissue. Here, we show that slit1 and slit2, known chemorepellents for RGC axons expressed in specific regions of the diencephalon and telencephalon, help regulate optic tract development. In mice lacking slit1 and slit2, a subset of RGC axons extend into the telencephalon and grow along the pial surface but not more deeply into this tissue. Surprisingly, distinct guidance errors occur in the telencephalon of slit1 -/-; slit2 +/- and slit1/2 -/- embryos, suggesting that the precise level of Slits is critical for determining the path followed by individual axons. In mice lacking both slit1 and slit2, a subset of RGC axons also project aberrantly into the epithalamus, pineal and across the dorsal midline. However, many axons reach their primary target, the superior colliculus. This demonstrates that Slits play an important role in directing the guidance of post-crossing RGC axons within the optic tracts but are not required for target innervation.

Animals↗
PubMed2002

Laminar disorganisation of mitral cells in the olfactory bulb does not affect topographic targeting of primary olfactory axons.

Primary olfactory neurons expressing the same odorant receptor protein typically project to topographically fixed olfactory bulb sites. While cell adhesion molecules and odorant receptors have been implicated in guidance of primary olfactory axons, the postsynaptic mitral cells may also have a role in final target selection. We have examined the effect of disorganisation of the mitral cell soma layer in mutant mice heterozygous for the beta-subunit of platelet activating factor acetylhydrolase (Lis1(-/+)) on the targeting of primary olfactory axons. Lis1(-/+) mice display abnormal lamination of neurons in the olfactory bulb. Lis1(-/+) mice were crossed with the P2-IRES-tau:LacZ line of transgenic mice that selectively expresses beta-galactosidase in primary olfactory neurons expressing the P2 odorant receptor. LacZ histochemistry revealed blue-stained P2 axons that targeted topographically fixed glomeruli in these mice in a manner similar to that observed in the parent P2-IRES-tau:LacZ line. Thus, despite the aberrant organisation of postsynaptic mitral cells in Lis1(-/+) mice, primary olfactory axons continued to converge and form glomeruli at correct sites in the olfactory bulb. Next we examined whether challenging primary olfactory axons in adult Lis(-/+) mice with regeneration would affect their ability to converge and form glomeruli. Following partial chemical ablation of the olfactory neuroepithelium with dichlobenil, primary olfactory neurons die and are replaced by newly differentiating neurons that project axons to the olfactory bulb where they converge and form glomeruli. Despite the aberrant mitral cell layer in Lis(-/+) mice, primary olfactory axons continued to converge and form glomeruli during regeneration. Together these results demonstrate that the convergence of primary olfactory axons during development and regeneration is not affected by gross perturbations to the lamination of the mitral cell layer. Thus, these results support evidence from other studies indicating that mitral cells do not play a major role in the convergence and targeting of primary olfactory axons in the olfactory bulb.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1997

Sensory nociceptive axons invade the cerebellum of transgenic mice overexpressing nerve growth factor.

Transgenic mice possessing elevated levels of mRNA expression and synthesis for the neurotrophin nerve growth factor among astrocytes display a robust ingrowth of new sympathetic fibers to the cerebellum. In this investigation, we report that the cerebellum of these mice also possesses a dense plexus of aberrant axons of sensory origin. Axons stained immunohistochemically for calcitonin gene-related peptide were seen in the transgenic cerebellum as early as one week after birth. The density of these axons dramatically increased with age. Immunopositive axons were confined predominantly to the deep white matter of the cerebellum in the adult transgenic mice, with a smaller number of axons seen coursing along blood vessels in the gray matter. Axons stained immunohistochemically for the neurotrophin receptor, p75NTR, displayed a similar pattern of distribution and density as those immunostained for calcitonin gene-related peptide. Wild-type post-natal and adult animals lacked such calcitonin gene-related peptide- and p75NTR-immunoreactive axons in the cerebellum. Retrograde labelling revealed that these axons within the transgenic cerebellum originated from neurons in the sensory trigeminal and dorsal root ganglia (upper cervical levels). This investigation demonstrates that overexpression of nerve growth factor is capable of inducing the directional growth of collateral axons of sensory neurons into the undamaged mammalian central nervous system.

Animals↗
PubMed2003

Diffusible signals and fasciculated growth in reticulospinal axon pathfinding in the hindbrain.

We have addressed the control of longitudinal axon pathfinding in the developing hindbrain, including the caudal projections of reticular and raphe neurons. To test potential sources of guidance signals, we assessed axon outgrowth from embryonic rat hindbrain explants cultured in collagen gels at a distance from explants of midbrain-hindbrain boundary (isthmus), caudal hindbrain, or cervical spinal cord. Our results showed that the isthmus inhibited caudally directed axon outgrowth by 80% relative to controls, whereas rostrally directed axon outgrowth was unaffected. Moreover, caudal hindbrain or cervical spinal cord explants did not inhibit caudal axons. Immunohistochemistry for reticular and raphe neuronal markers indicated that the caudal, but not the rostral projections of these neuronal subpopulations were inhibited by isthmic explants. Companion studies in chick embryos showed that, when the hindbrain was surgically separated from the isthmus, caudal reticulospinal axon projections failed to form and that descending pioneer axons of the medial longitudinal fasciculus (MLF) play an important role in the caudal reticulospinal projection. Taken together, these results suggest that diffusible chemorepellent or nonpermissive signals from the isthmus and substrate-anchored signals on the pioneer MLF axons are involved in the caudal direction of reticulospinal projections and might influence other longitudinal axon projections in the brainstem.

Animals↗
PubMed2003

Reciprocal interactions between olfactory receptor axons and olfactory nerve glia cultured from the developing moth Manduca sexta.

In olfactory systems, neuron-glia interactions have been implicated in the growth and guidance of olfactory receptor axons. In the moth Manduca sexta, developing olfactory receptor axons encounter several types of glia as they grow into the brain. Antennal nerve glia are born in the periphery and enwrap bundles of olfactory receptor axons in the antennal nerve. Although their peripheral origin and relationship with axon bundles suggest that they share features with mammalian olfactory ensheathing cells, the developmental roles of antennal nerve glia remain elusive. When cocultured with antennal nerve glial cells, olfactory receptor growth cones readily advance along glial processes without displaying prolonged changes in morphology. In turn, olfactory receptor axons induce antennal nerve glial cells to form multicellular arrays through proliferation and process extension. In contrast to antennal nerve glia, centrally derived glial cells from the axon sorting zone and antennal lobe never form arrays in vitro, and growth-cone glial-cell encounters with these cells halt axon elongation and cause permanent elaborations in growth cone morphology. We propose that antennal nerve glia play roles similar to olfactory ensheathing cells in supporting axon elongation, yet differ in their capacity to influence axon guidance, sorting, and targeting, roles that could be played by central olfactory glia in Manduca.

Actins↗
PubMed2003

Glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor sustain the axonal regeneration of chronically axotomized motoneurons in vivo.

In contrast to injuries in the central nervous system, injured peripheral neurons will regenerate their axons. However, axotomized motoneurons progressively lose their ability to regenerate their axons, following peripheral nerve injury often resulting in very poor recovery of motor function. A decline in neurotrophic support may be partially responsible for this effect. The initial upregulation of glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) by Schwann cells of the distal nerve stump after nerve injury has led to the speculation that they are important for motor axonal regeneration. However, few experiments directly measure the effects of exogenous BDNF or GDNF on motor axonal regeneration. This study provided the first direct and quantitative evidence that long-term continuous treatment with exogenous GDNF significantly increased the number of motoneurons which regenerate their axons, completely reversing the negative effects of chronic axotomy. The beneficial effect of GDNF was not dose-dependent. A combination of exogenous GDNF and BDNF on motor axonal regeneration was significantly greater than either factor alone, and this effect was most pronounced following long-term continuous treatment. The ability of GDNF, either alone or in combination with BDNF, to increase the number of motoneurons that regenerated their axons correlated well with an increase in axon sprouting within the distal nerve stump. Thus long-term continuous treatment with neurotrophic factors, such as GDNF and BDNF, can be used as a viable treatment to sustain motor axon regeneration.

Animals↗
PubMed2003

Glial cell line-derived neurotrophic factor-enriched bridging transplants promote propriospinal axonal regeneration and enhance myelination after spinal cord injury.

Glial cell line-derived neurotrophic factor (GDNF), a distant member of the transforming growth factor-beta (TGF-beta) family, is widely expressed in the developing and adult central nervous system (CNS). At present, limited information is available regarding the effects of GDNF in the repair of spinal cord injury (SCI). In the present study, mini-guidance channels containing either: (1) Matrigel (MG, a basement membrane component), (2) Schwann cells (SCs, 120 x 10(6)/ml) in MG (SC-MG), (3) recombinant human GDNF (rhGDNF, 3 microg/microl) in MG (GDNF-MG), and (4) a combination of all three components (GDNF-SC-MG) were grafted into a T9 hemisection-gap lesion in adult rats to examine the effects of GDNF on axonal regeneration and myelination following SCI. Thirty days post-transplantation, limited axonal growth was observed within guidance channels containing MG-alone (MG). When SCs were added to the channels (SC-MG group), consistent axonal ingrowth containing both myelinated and unmyelinated axons was observed, confirming our previous findings. The addition of GDNF-alone without SCs (GDNF-MG) resulted in substantial ingrowth of unmyelinated axons, suggesting that GDNF has a direct neurite-growth promoting effect on these axons. Implantation of channels containing both GDNF and SCs (GDNF-SC-MG) produced a significant and synergistic increase in axonal regeneration and myelination. In addition, GDNF reduced the extent of reactive gliosis, infiltration of activated macrophages/microglia, and cystic cavitation at the graft-host interfaces. Retrograde tracing revealed that grafts of SC-seeded channels containing GDNF promoted a significant increase in the number of propriospinal neurons which had regenerated their axons into the grafts, as compared to SC-MG-seeded channels. These results indicate that GDNF may play a novel therapeutic role in promoting propriospinal axonal regeneration, enhancing myelin formation, and improving graft-host interfaces after SCI.

Animals↗
PubMed1990

Temporal retinal growth cones collapse on contact with nasal retinal axons.

The behavior of retinal ganglion cell growth cones was examined as they met retinal ganglion cell axons in culture. All possible pairings of growth cones and axons from the ventral-nasal, ventral-temporal, and dorsal-temporal quadrants of the chick retina were examined. Growth cones grow across axons with little difficulty in all those combinations in which nasal growth cones meet either nasal or temporal axons or temporal growth cones meet temporal axons. However, temporal growth cones generally collapse on contact with nasal axons and thereby experience great difficulty in crossing them. These results are consistent with the hypothesis that nasal axons have associated with them a cue that (i) interferes with temporal growth cone motility, (ii) is absent on temporal axons, and (iii) is not recognized by nasal growth cones. This finding may explain why temporal growth cones prefer to grow on temporal as opposed to nasal axons, while nasal growth cones display no such preference.

Animals↗
PubMed2003

Axonal loss in the pathology of MS: consequences for understanding the progressive phase of the disease.

Axonal degeneration has been identified as the major determinant of irreversible neurological disability in patients with multiple sclerosis (MS). Axonal injury begins at disease onset and correlates with the degree of inflammation within lesions, indicating that inflammatory demyelination influences axon pathology during relapsing-remitting MS (RR-MS). This axonal loss remains clinically silent for many years, and irreversible neurological disability develops when a threshold of axonal loss is reached and compensatory CNS resources are exhausted. Experimental support for this view-the axonal hypothesis-is provided by data from various animal models with primary myelin or axonal pathology, and from pathological or magnetic resonance studies on MS patients. In mice with experimental autoimmune encephalomyelitis (EAE), 15-30% of spinal cord axons can be lost before permanent ambulatory impairment occurs. During secondary progressive MS (SP-MS), chronically demyelinated axons may degenerate due to lack of myelin-derived trophic support. In addition, we hypothesize that reduced trophic support from damaged targets or degeneration of efferent fibers may trigger preprogrammed neurodegenerative mechanisms. The concept of MS as an inflammatory neurodegenerative disease has important clinical implications regarding therapeutic approaches, monitoring of patients, and the development of neuroprotective treatment strategies.

Animals↗
PubMed1997

Intrinsic properties and environmental factors in the regeneration of adult cerebellar axons.

The success of axon regeneration in the adult mammalian brain depends on the presence of growth-permissive environmental conditions as well as on specific properties of the affected neurons. To investigate the relative contribution of extrinsic cues and intrinsic determinants to reparative processes we have investigated the regenerative properties of olivocerebellar and Purkinje cell axons. When these axon populations are severed in the cerebellar white matter and confronted with embryonic neural grafts of cerebellar or extracerebellar origin, the former vigorously regenerate into the transplant, whereas the latter invariably fail to do so (Rossi et al., 1995). The same response occurs when dissociated Schwann cells are implanted in the lesion site: Purkinje cell axons fail to regrow, whereas olivocerebellar fibres regenerate for considerable distances. Within the graft, regenerating fibres follow tortuous courses along Schwann cell bundles and sometimes end with poorly developed terminal plexuses. Some of them, however, succeed in crossing the graft and grow further into the host cortex, where they break into fine terminal branches confined to the granular layer. The remarkable regenerative response of olivocerebellar axons revealed by these experiments might be an intrinsic reaction of the affected neurons to axon injury or it might be elicited by growth promoting cues derived from the grafts. To elucidate this point we have undertaken the investigation of cellular changes occurring in adult inferior olivary neurons following the transection of the inferior cerebellar peduncle. Our results show that axotomy induces a series of cellular changes, or reparative and regressive character, which ultimately lead to cell death. Interestingly, however, these modifications are not uniformly distributed throughout the whole inferior olive. (i) Neuronal atrophy and degeneration progress more rapidly in the PO and DAO than in the MAO. (ii) A subpopulation of inferior olivary neurons become reactive for NADPH-diaphorase histochemistry, and their preferential localisation in the MAO suggests that this modification is related to the longer survival of these cells after axotomy. (iii) The developmentally regulated calcitonin gene-related peptide (CGRP) is reexpressed by a subset of neurons in the caudal nuclear compartments. These results further emphasise the conclusion that the dissimilar regenerative response of Purkinje cell and olivocerebellar axons confronted with permissive environmental conditions is due to different intrinsic properties of these neuronal populations. The reexpression of developmentally regulated substances by axotomised inferior olivary neurons suggests that their reparative reaction is triggered by axon injury. However, the pattern of growth of regenerating olivocerebellar axons is strongly conditioned by environmental constraints, which, in the present experimental conditions, do not allow them to reattain denervated Purkinje cells.

Animals↗
PubMed2000

The course of later generated axons in the developing optic nerve of the chick embryo. A morphometric electron microscopic study.

The topographic position of growth cones (GCs) shows the course of ingrowing axons within the optic nerve and allows to draw conclusions with respect to the fiber order in this pathway. Therefore, the topographic distribution and frequency of GCs as well as the proximal and distal axon shaft segments were studied within cross-sections of the distal, middle, and prechiasmatic part of the nerve of 3-8-day-old embryos using electron microscopy. The ingrowth of GCs was not confined to a particular region. Initially, GCs were found near the ventral periphery. With increasing age, simultaneous ingrowth occurred within an area that expanded dorsally. In parallel, GCs also occurred in dorsal regions and eventually in the dorsal periphery. GCs intermingled everywhere with more mature axon profiles. However, youngest profiles predominated ventrally, oldest dorsally. Hence, maturity increased from ventral to dorsal. This indicated that the time of arrival of axons and the topographic position in the cross-section correlated significantly. It is concluded that axons are chronotopically organized, but in a probabilistic sense. The predominant ingrowth of axons in the ventral part may be associated largely with the first wave of neurogenesis of retinal ganglion cells. The ingrowth in dorsal regions of the cross section may be related to later generated axons that enter the nerve following older axons of the same retinal sector as well as axons of neighboring ganglion cells which continue to leave the mitotic cycle while the front of neurogenesis has spread into the periphery.

Animals↗
PubMed2003

Dynamic compartmentalization of the voltage-gated sodium channels in axons.

One of the major physiological roles of the neuronal voltage-gated sodium channel is to generate action potentials at the axon hillock/initial segment and to ensure propagation along myelinated or unmyelinated fibers to nerve terminal. These processes require a precise distribution of sodium channels accumulated at high density in discrete subdomains of the nerve membrane. In neurons, information relevant to ion channel trafficking and compartmentalization into sub-domains of the plasma membrane is far from being elucidated. Besides, whereas information on dendritic targeting is beginning to emerge, less is known about the mechanisms leading to the polarized distribution of proteins in axon. To obtain a better understanding of how neurons selectively target sodium channels to discrete subdomains of the nerve, we addressed the question as to whether any of the large intracellular regions of Nav1.2 contain axonal sorting and/or clustering signals. We first obtained evidence showing that addition of the cytoplasmic carboxy-terminal region of Nav1.2 restricted the distribution of a dendritic-axonal reporter protein to axons of hippocampal neurons. The analysis of mutants revealed that a di-leucine-based motif mediates chimera compartmentalization in axons and its elimination in soma and dendrites by endocytosis. The analysis of the others generated chimeras showed that the determinant conferring sodium channel clustering at the axonal initial segment is contained within the cytoplasmic loop connecting domains II-III of Nav1.2. Expression of a soluble Nav1.2 II-III linker protein led to the disorganization of endogenous sodium channels. The motif was sufficient to redirect a somatodendritic potassium channel to the axonal initial segment, a process involving association with ankyrin G. Thus, it is conceivable that concerted action of the two determinants is required for sodium channel compartmentalization in axons.

Amino Acid Motifs↗