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PubMed1986

Changes in the organization of the neuritic cytoskeleton during nerve growth factor-activated differentiation of PC12 cells: a serial electron microscopic study of the development and control of neurite shape.

After exposure to nerve growth factor, PC12 cells differentiate within a period of only a few days into cholinergic sympathetic neurons. Using computer-assisted three-dimensional serial electron microscopic reconstruction, we describe the progressive cytoskeletal and structural changes of PC12 neurites at different stages in their differentiation. Developmental changes in these neurites can be characterized by two major transitions. First, microtubules (MTs), which define the longitudinal axis of the neurite, increase in number leading to a more cylindrical and uniform neurite shape. Second, there are major changes in the relative numbers of other organelle types, which reflect the functional specialization of the neurite. These changes do not in themselves seriously affect shape change of the neurite during development, however the presence of these organelles and their associated obligatory volumes (volumes surrounding organelle) account for well over 50% of the neurite's volume at all stages of development. The MT-MT distances and obligatory volumes associated with the organelles remain constant throughout development. Thus, we can conclude that many of the observed changes seen in developing PC12 neurites are due simply to the production of a greater number of MTs in the cell, and that many of the other important parameters that can be measured and contribute to neurite shape remain constant during development.

Animals↗

PubMed2005

Effects of soluble laminin on organelle transport and neurite growth in cultured mouse dorsal root ganglion neurons: difference between primary neurites and branches.

Laminin, an extracellular matrix molecule, is known to promote neurite growth. In the present study, the effects of soluble laminin on organelle transport and their relation to neurite growth were investigated in cultured dissociated mouse dorsal root ganglion (DRG) neurons. Laminin added into the extracellular medium was deposited on the surface of DRG neurons. DRG neurons incubated with soluble laminin exhibited branched, long, and thin neurites. Time-lapse study demonstrated that many small-diameter branches were newly formed after the addition of laminin. Thus, the growths of large-diameter primary neuritis, arising from cell bodies and branches extended from growth cones of primary neuritis, were analyzed separately. Laminin decreased the growth rate of primary neurites but increased that of branches. In primary neurites, acute addition of laminin rapidly decreased organelle movement in the neurite shaft and growth cone, accompanied by slowing of the growth cone advance. Branching of primary neurites occurred in response to laminin in some growth cones. In these growth cones, organelles protruded into nascent branches. In branches, soluble laminin increased organelle movement in the growth cone and the distal portion of the shaft. These results suggest that laminin inhibits the elongation of primary neurites but promotes branching and elongation of branches, all of which seem to be closely related to organelle transport.

Animals↗

PubMed2002

Recombinant human heparin-binding neurite-promoting factor expressed with yeast stimulates neurites outgrowth.

OBJECTIVES: Heparin-binding neurite-promoting factor (HBNF) is a heparin-binding protein primarily found in the brain, which can stimulate neurite outgrowth in vitro. We expressed recombinant human heparin-binding neurite-promoting factor (hrHBNF) using a yeast system, and observed its activity in stimulating neurite outgrowth in vitro. METHODS: cDNA encoding mature human HBNF was amplified from total RNA isolated from an 18-week aborted human fetal brain by RT-PCR method. After amplification, the HBNF cDNA gene was cloned into pPIC9K, a shuttle expression vector for yeast system. The positive clone of expression vector bearing HBNF cDNA gene was obtained by screening. Verified recombinant vector was then used to transform Pichia strain GS115 by electroporation. His(+) transformants were selected on minimal dextrose medium (MD) plates which were histidine free. His(+) yeast recombinants with multi-copy inserts were screened in vivo by their resistance to G418. PCR analysis was used to confirm the integration of the HBNF cDNA gene into the Pichia genome. Secreted expression of hrHBNF protein in culture medium was obtained when the positive clone containing the HBNF cDNA gene was induced by methanol. The hrHBNF product purified by gel chromatography was added to cultured rat pheochromocytoma (PC12) cells to observe its ability to stimulate neurite outgrowth. RESULTS: In the recombinant expression vector, the insert was sequenced to show exactly the sequence encoding human HBNF according to Genbank data. The HBNF cDNA gene was cloned downstream to the alpha-factor, and its open reading frame was in frame with the alpha-factor signal sequence in pPIC9K. SDS-PAGE showed that the molecular weight of the induced expression product was about 18 kDa, consistent with that of human HBNF reported in the literature. The protein product did promote neurite outgrowth in cultured rat pheochromocytoma (PC12) cells. CONCLUSION: Recombinant human heparin-binding neurite-promoting factor can be expressed with a yeast system, and its product possesses the biological activity to promote neurite outgrowth.

Animals↗

PubMed1989

Analysis of slow-onset neurite formation in NG108-15 cells: implications for a unified model of neurite elongation.

When undifferentiated NG108-15 cells are plated onto polylysine coated Petri dishes in serum-free medium, they form neurites within 1-4 h if plated in the presence of laminin or 5'-deoxy-5'-methylthioadenosine (rapid-onset neurites). In the absence of such agents, serum-deprived NG108-15 cells extend axon-like neurites onto polylysine over several days; here we characterize the dynamic behavior of this slow-onset outgrowth pattern in detail. Individual cells plated on laminin expressed a gradual multipolar-to-unipolar transition due to rapid-onset neurites becoming remodelled into the appearance of slow-onset neurites. This phenomenon reflected the selective stabilization of certain rapid-onset neurites, along with the restriction of motility to their distal tips. Based upon the properties and interactions of both rapid- and slow-onset neurites in NG108-15 cells, a unified model for neurite formation is presented.

Animals↗

PubMed1986

NIF (neurite-inducing factor): a novel peptide inducing neurite formation in PC12 cells.

Neurite-inducing factor (NIF) is a novel protein that has been partially purified from mouse submaxillary glands. NIF induces neurite formation in PC12 pheochromocytoma cells, and the NIF-induced neurites are indistinguishable from NGF-induced neurites in both their morphology and the time course of their formation. Neurite-inducing activity can be recovered at a position corresponding to a molecular weight of 20,000 Da after fractionation of partially purified preparations via SDS-PAGE. Partially purified preparations of NIF are about half as potent as pure beta NGF, and since the neurite-inducing activity does not correspond to any of the major proteins in this fraction, specific activity of purified NIF will probably be significantly greater than the 60 ng/ml found for our partially purified material. NIF is distinct from beta NGF by four criteria: (1) antibodies to beta NGF can block the activity of beta NGF, but not the activity of NIF; (2) beta NGF can induce ornithine decarboxylase (ODC) in PC12 cells at concentrations significantly below those required to induce neurites, while NIF induces ODC only at concentrations greatly in excess of those required to induce neurite formation; (3) by the criterion of SDS-PAGE, there is insufficient beta NGF in our partially purified preparations of NIF to explain the biological activity of this fraction; and (4) the biological activity of NIF has a molecular weight (20,000 Da) that is distinct from beta NGF (13,000 Da). We conclude that NIF is probably a novel peptide that is very active in promoting morphological differentiation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Gland Neoplasms↗

PubMed1985

Neurite guidance by non-neuronal cells in culture: preferential outgrowth of peripheral neurites on glial as compared to nonglial cell surfaces.

Growing axons in the peripheral nervous system (PNS) encounter a variety of cellular and extracellular substrates. Since it is difficult to sort out the possible contributions of these diverse components of the extracellular environment to axonal guidance in vivo, I have developed an in vitro system to study neurite outgrowth on two classes of cells which may provide as substrates for growing axons during development or regeneration: glial cells, e.g., astrocytes and Schwann cells, and nonglial cells, e.g., fibroblasts. Although neurites from sympathetic and spinal sensory ganglia explants grew onto preformed monolayers of both glial and nonglial cells, glial cells were a markedly better substrate. On the glial cells the neurites extended at a rate of 25 to 30 micron/hr and traveled singly or in fine fascicles; their growth cones displayed long filopodia and migrated on the upper surface of the monolayer cells. Conditioned media experiments suggested that neurite outgrowth on glial cell monolayers was not mediated by soluble secreted factors. These results indicate that the glial cell surface is an attractive substrate for neurite outgrowth. In contrast, on nonglial cells the rate of outgrowth was only 10 to 15 micron/hr, large neurite fascicles were common, and the growth cones migrated beneath the monolayer cells in contact with the underlying artificial substrate. This location of the growth cone, coupled with the observation that conditioned medium from these cells promoted neurite outgrowth only when bound to artificial substrates, suggests that secreted substrate-associated components may be an important determinant of neurite outgrowth on nonglial cell monolayers.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1982

Conditioned medium increases the rate of neurite elongation: separation of this activity from the substratum-bound inducer of neurite outgrowth.

Heart cell-conditioned medium supports extensive neurite outgrowth from dissociated parasympathetic neurons of the chicken embryo ciliary ganglion. We have shown previously that neurite outgrowth in this system depends on the deposition of a substratum-conditioning factor from conditioned medium onto the polyornithine culture substratum. However, in the presence of only the substratum-bound material, neurite outgrowth is never as extensive as in whole conditioned medium. The present report demonstrates that a different and soluble component of conditioned medium is required to achieve the rates of neurite elongation normally observed in whole conditioned medium. This second component, while unable by itself to support neurite outgrowth, is able to increase the rate of neurite elongation approximately 3-fold within 30 to 60 min of its addition. This conclusion is based on direct time-lapse observations of the rate of elongation of individual neurites before and after the addition of fractions of conditioned medium previously depleted of the substratum-conditioning factor. Correlated with the effect of such fractions of conditioned medium on the rate of neurite elongation is a change in the morphology of the growth cones, which become larger and more spread. The activity of the soluble, elongation-promoting component of conditioned medium is nondialyzable and is sensitive to treatments known to affect proteins, such as repeated freeze-thawing, heating, and trypsinization. Fractions of conditioned medium which contain the elongation-promoting activity also contain all of the survival factor for parasympathetic neurons previously shown to be present in heart cell-conditioned medium. The methods described here represent a convenient new assay which we have used recently to demonstrate elongation-promoting factors with neuronal specificity in extracts of rat hippocampus.

Animals↗

PubMed2004

Neuro-p24 plays an essential role in neurite extension: antisense oligonucleotide inhibition of neurite extension in cultured DRG neurons and neuroblastoma cells.

Neuro-p24 is a novel neuronal membrane protein that is specifically localized in neural processes, particularly in growing neurites. To explore the roles of Neuro-p24, we examined the immunocytochemical localization of this protein in cultured neurons during neural induction, and performed an antisense oligonucleotide transfection using two culture models, the mouse dorsal root ganglia (DRG) and the neuro2a neuroblastoma cell line. Intense Neuro-p24 immunoreactivity was observed in the soma and small vesicles in neurites at the early stage of culture, but it gradually disappeared as cultures proceeded. Intense immunoreactivity was often observed at the growing distal end of the neurites. Morphological changes in neurites after Neuro-p24 antisense oligonucleotide transfection were examined in DRG neurons by the continual observation of a group of identical neurons. Affected cells retracted neurites transiently, followed by the re-elongation and branching of newly formed neurites. The control oligonucleotide-treated neurons appeared unaffected. When neuro2a cells were similarly treated with antisense oligonucleotides, the results were similar to those obtained in the DRG neurons. The binding of Neuro-p24 to tubulin was confirmed by both in vivo and in vitro pull-down assays. The present results support our idea that Neuro-p24 plays an essential role in neurite extension through a vesicle transport system via microtubules.

Animals↗

PubMed1996

Lysophosphatidic acid-induced neurite retraction in PC12 cells: neurite-protective effects of cyclic AMP signaling.

Effects of the cyclic AMP second messenger system were studied on the retraction of neurites elicited by the phospholipid mediator lysophosphatidic acid (LPA) in PC12 cells. LPA stimulation inhibited adenylyl cyclase, indicating that the LPA receptor couples to the heterotrimeric Gi proteins. However, pertussis toxin or expression of dominant negative Ras did not prevent neurite retraction. In contrast, cholera toxin, forskolin, and application of dibutyryl-cyclic AMP prevented neurite retraction. The neurite-protective effect of forskolin was blocked by Rp-adenosine 3',5'-phosphorothioate. Forskolin and dibutyryl-cyclic AMP both failed to protect neurites in A126-1B2 and 123.7 cells, which lack cyclic AMP-activated protein kinase. Data indicate that elevation of cyclic AMP levels triggers a cyclic AMP-activated protein kinase-dependent mechanism that opposes the functioning of the morphoregulatory signaling activated by LPA. ADP-ribosylation of Rho by the Clostridium botulinum C-3 toxin in 123.7 cells caused neuronal differentiation, indicated by neurite extension, and blocked LPA-induced neurite retraction. LPA activates Gq- and Gi-linked signaling in parallel; therefore, a morphoregulatory signaling network hypothesis is proposed versus the simplistic approach of a signaling pathway. The signaling network integrates the receptor-activated individual, sequential, and parallel signaling events into an interactive network whose individual components may fulfill required and permissive functions encoding the cellular response.

ADP Ribose Transferases↗

PubMed1997

Alpha 1-tubulin mRNA level is increased during neurite outgrowth of NG 108-15 cells but not during neurite outgrowth inhibition by CNS myelin.

alpha 1-tubulin is an isotype of alpha-tubulin, and its mRNA is expressed in the rodent nervous system. A high level of alpha 1-tubulin mRNA in neurones is associated with axonal outgrowth during development as well as with axonal regeneration after axotomy in adult animals. We quantitated alpha 1-tubulin mRNA levels in motor neurone-like NG 108-15 cells using Northern blots in order to determine whether the expression of this neurite outgrowth-associated gene is regulated in NG 108-15 cells during neurite extension and during inhibition of this process by CNS myelin. Here we report that during the acute phase of neurite outgrowth, alpha 1-tubulin mRNA level increases in NG 108-15, a maximal induction of 1.7-fold over the initial level occurring 24 h after neurite outgrowth onset. By contrast, when these cells are plated on CNS myelin alpha 1-tubulin mRNA levels show no such increase. These findings indicate that an increase of the alpha 1-tubulin mRNA level is associated with neurite outgrowth of NG 108-15 cells. More interestingly, this study also demonstrates that the inhibition of neurite outgrowth by CNS myelin may affect the expression of a gene encoding a protein involved in neurite extension.

Animals↗

PubMed1984

The possible role of "sibling neurite bias" in the coordination of neurite extension, branching, and survival.

In this review we consider a novel mechanism, "sibling neurite bias," which may explain aspects of the coordination of elongation, branching, and resorption among different neurites growing from the same neuronal cell body. In this model, growing neurites which incorporate structural precursors at higher rates would deplete the cellular pool of precursors available to their "sibling" neurites; neurites would compete for survival, but in addition they would bias each other's behavior during active growth. Evidence is reviewed that "sibling neurite bias" may contribute to the establishment and stabilization of specific neural connections. Specific examples examined include the loss of polyinnervation at the developing neuromuscular junction, contextual mapping in the retino-tectal system, and selective neurite growth patterns and synaptic connections in nerve tissue culture model systems.

Animals↗

PubMed1984

Antiserum against neurite outgrowth factor in chick gizzard extract and its inhibitory effect on neuritic response in cultured ciliary neurons.

Antiserum against a neurite outgrowth factor (NOF) of gizzard extract that promotes neurite outgrowth from dissociated ciliary ganglionic neurons (CG neurons) of 8-day-old chick embryo was prepared to determine whether or not the antiserum inhibits neurite outgrowth from cultured neurons or explants of chick and murine tissues. When CG neurons were cultured on a polyornithine-coated well exposed to NOF (NOF-bound POR well), marked neurite outgrowth was observed. When NOF-bound POR wells were exposed to antiserum, neurite outgrowth from CG neurons was gradually inhibited with increasing amounts of antiserum, while exposure to preimmune serum did not prevent neurite outgrowth. Antiserum had no effect on neuronal survival during a 48-h incubation. The diluted antiserum, which produced nearly 100% inhibition of the NOF activity, was almost equally active in suppressing the activity of NOFs in conditioned media (CM) of various chick embryo tissues, but showed much less inhibitory effects on NOFs in CM of murine tissues. The appearance of neurites from explants of spinal cord, dorsal root ganglion, or retina of chick embryo was also inhibited by the antiserum. These results indicate that antiserum against NOF from gizzard extract suppressed the activity of NOFs from various sources, and that there are species differences in NOFs, at least between chick and murine.

Animals↗

PubMed1994

An extensive network of PHF tau-rich dystrophic neurites permeates neocortex and nearly all neuritic and diffuse amyloid plaques in Alzheimer disease.

Previous studies demonstrated paired helical filament tau (PHF tau) in neuritic but not diffuse beta-amyloid (A beta) plaques in Alzheimer's disease (AD). Re-examination of amyloid deposits with antibodies to A beta and PHF tau by conventional and confocal microscopy using double label immunohistochemistry showed that PHF tau is a component of both diffuse and neuritic plaques in AD. Unlike controls, a dense network of PHF tau positive dystrophic neurites extended throughout the AD neocortex permeating nearly all neuritic and diffuse plaques. Thus, PHF tau-rich dystrophic neurites are common components of neuritic and diffuse plaques in AD neocortex.

Aged↗

PubMed1996

Directional neurite outgrowth and axonal differentiation of embryonic hippocampal neurons are promoted by a neurite outgrowth domain of the B2-chain of laminin.

Molecular cues involved in directional neurite outgrowth and axonal differentiation of embryonic hippocampal neurons were studied on substrates coated in a striped 5 microns pattern with synthetic peptides from a neurite outgrowth (RDIAEIIKDI, P1543) and cell attachment (CDPGYIGSR, P364) domain of the B2- and B1-chains of laminin, respectively. Both peptides supported neuronal attachment, but only the B2-chain-derived P1543 promoted expression of a mature neuronal phenotype. Directional neurite outgrowth and axonal differentiation of embryonic hippocampal neurons were selectively induced by striped substrates of the B2-chain-derived P1543. Axonal differentiation was determined by expression of a phosphorylated epitope of the 200 kDa neurofilament protein in the longer "axonal" neurite of the bipolar embryonic hippocampal neurons. Ethanol (100 mM), a neuroactive compound known to delay neuronal development, impaired both directional neurite outgrowth and expression of a phosphorylated epitope of the 200 kDa neurofilament protein on a patterned P1543 substratum. The present results provide direct evidence that a 10 amino acid peptide (P1543), derived from a neurite outgrowth domain of the B2-chain of laminin, may be an axonal guidance and differentiation factor for embryonic hippocampal neurons in vitro.

Animals↗

PubMed1985

Comparison of the effects of laminin and the polyornithine-binding neurite promoting factor from RN22 Schwannoma cells on neurite regeneration from cultured newborn and adult rat dorsal root ganglion neurons.

We have investigated the effects of two neurite promoting factors (NPFs)--laminin and the semipurified polyornithine-binding neurite promoting factor (PNPF-1) from RN 22 Schwannoma cells--on neurite regeneration from dissociated newborn and adult rat dorsal root ganglion (DRG) neurons during 24 and 48 h culture periods in the absence of exogenous neuronotrophic factors. Both laminin and PNPF, when used to pretreat the polyornithine substratum, significantly enhanced neurite recruitment from surviving newborn and adult DRG neurons as compared to an untreated polyornithine substratum. However, the responses of newborn neurons at saturating concentrations of laminin and PNPF were consistently greater (46% neurite-bearing cells at 24 h, 81% at 48 h) than those of adult neurons (14 and 45%, respectively). The responsive neurons of both newborn and adult DRG displayed extensive neuritic networks at 48 h. The ED50 of laminin, or PNPF was 0.15-0.2 micrograms/ml for both newborn and adult neurons. The similarities in the responses of newborn and adult DRG neurons to NPFs validate the use of neurons from embryonic and newborn animals for the in vitro assays of NPFs that can be collected from injured and regenerating adult peripheral nervous tissues.

Age Factors↗

PubMed1986

Experimental modification of PC12 neurite shape with the microtubule-depolymerizing drug Nocodazole: a serial electron microscopic study of neurite shape control.

The microtubule-depolymerizing drug Nocodazole has been used to experimentally manipulate the form of PC12 neurites. Both time-lapse photography and serial electron microscopy demonstrate that microtubule depolymerization leads to varicosity formation due to a clustering of membranous organelles in young neurites (nerve growth factor activated within 7 d). Neurites that have been nerve growth factor activated 7 or more d before Nocodazole application are resistant to microtubule depolymerization. These data and data from previous papers has been combined in an attempt to predict quantitatively the volume and the shape of a neurite. The relationship is described mathematically by Vn = 4.52 Vo + 0.0054 MTl, where Vn is local neurite volume, Vo is organelle volume, and MTl is MT length (the constant, 0.0054 is micron2), and 4.52 is the obligatory volume constant derived from serial electron microscopic studies. The equation predicts the total volume of neurites despite alterations of morphology due to Nocodazole and despite changes in morphology during development.

Animals↗

PubMed1999

Glycogen Synthase Kinase-3 Modulates Neurite Outgrowth in Cultured Neurons: Possible Implications for Neurite Pathology in Alzheimer's Disease.

Glycogen synthase kinase-3 (GSK-3) is thought to play an important role in the hyperphosphorylation of tau, and possibly other proteins, in Alzheimer's disease (AD). However, the effects of GSK-3 on neuronal metabolism are still largely unknown. Here we describe that a low concentration of lithium, which can partially inhibit endogenous GSK-3, favored the extension of neurites from developing neurons, whereas a high concentration of lithium impaired neurite growth. Furthermore, the overexpression of exogenous active GSK-3 in neurons by infection with a defective herpesviral vector blocked neurite growth, which was not affected by either expression of inactive GSK-3 or just the herpesviral vector infection. Neurite extension was restored when neurons overexpressing exogenous active GSK-3 were incubated with lithium. These results are consistent with a role for GSK-3 in the regulation of cytoskeletal dynamics during neurite growth. Accordingly, up-regulation of GSK-3 may contribute to cytoskeletal pathology within neurites in AD.

Journal Article↗

PubMed1994

Sense and antisense transfection analysis of tau function: tau influences net microtubule assembly, neurite outgrowth and neuritic stability.

Microtubules are fundamental elements participating in many aspects of cell behavior and maintenance, yet the factors regulating microtubule behavior in vivo remain poorly understood. Employing the nerve growth factor (NGF)-responsive cell line, PC12, we have used sense and antisense DNA transfection strategies to examine the role of the microtubule-associated protein (MAP) tau in several aspects of neuronal cell behavior. Stable transfectants over-expressing tau accumulate more microtubule mass and extend neurites more rapidly than control cells, while transfectants under-expressing tau exhibit reduced microtubule levels and slower neurite outgrowth. Further, tau over-expressing cells are markedly more resistant to nocodazole-induced neuritic degeneration when compared to wild-type or tau under-expressing cells. These observations provide direct support for the model that tau is capable of influencing: (i) net microtubule assembly, (ii) the rate of neurite elongation and (iii) neuritic stability. These capabilities suggest that tau plays crucial roles in the development and maintenance of neuronal cells.

Animals↗