Spatial requirements for TrkA kinase activity in the support of neuronal survival and axon growth in rat sympathetic neurons

At least 50% of the major axonal membrane lipid, phosphatidylcholine, of rat sympathetic neurons is synthesized in situ in axons [Posse de Chaves, Vance, Campenot and Vance (1995) J. Cell Biol. 128, 913-918]. In the same study we reported that, in a choline-deficient model for neuron growth, phosphatidylcholine synthesis in cell bodies is neither necessary nor sufficient for growth of distal axons. Rather, the local synthesis of phosphatidylcholine in distal axons is required for normal axon growth. We have now used three alkylphosphocholines (hexadecylphosphocholine, dodecylphosphocholine and octadecylphosphocholine) as inhibitors of PtdCho biosynthesis in a compartmented model for culture of rat sympathetic neurons. The experiments reveal that alkylphosphocholines decrease the uptake of choline into these neurons and inhibit PtdCho synthesis, but not via an effect on the activity of the enzyme CTP: phosphocholine cytidylyltransferase. We also show that when the distal axons, but not the cell bodies, are exposed to alkylphosphocholines, axonal elongation is inhibited, which is consistent with the hypothesis that phosphatidylcholine synthesis in axons, but not in cell bodies, is required for axonal elongation. The inhibitory effect of alkylphosphocholines on axon growth is most likely not mediated via a decrease in the activity of protein kinase C, since when this enzyme activity is down-regulated by treatment of the cells with phorbol ester, the alkylphosphocholines retain their ability to inhibit axonal growth.

Download Full-text

Vascular-derived artemin: a determinant of vascular sympathetic innervation?

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00859.2006 ◽

2007 ◽

Vol 293 (1) ◽

pp. H266-H273 ◽

Cited By ~ 21

Author(s):

Deborah H. Damon ◽

Jaclyn A. teRiele ◽

Stephen B. Marko

Keyword(s):

Important Determinant ◽

Sympathetic Neurons ◽

Sympathetic Innervation ◽

Axon Growth ◽

Neurite Growth ◽

Sympathetic Ganglia ◽

Neonatal Rat ◽

Rt Pcr ◽

Adult Rats ◽

Sympathetic Axon

Vascular sympathetic innervation is an important determinant of blood pressure and blood flow. The mechanisms that determine vascular sympathetic innervation are not well understood. The present study tests the hypothesis that vascular-derived artemin promotes the development of sympathetic innervation to blood vessels by promoting sympathetic axon growth. RT-PCR and Western analyses indicate that artemin is expressed by cultured vascular smooth muscle and arteries, and artemin coreceptors, glial cell-derived neurotrophic factor family receptor α3 and ret, are expressed by postganglionic sympathetic neurons. The effects of artemin on axon growth were assessed on explants of neonatal rat sympathetic ganglia. In the presence, but not in the absence, of nerve growth factor, exogenous artemin stimulated neurite growth. Femoral arteries (FA) from adult rats contain artemin, and these arteries stimulated sympathetic neurite growth. Growth in the presence of FA was 92.2 ± 11.9 mm, and that in the absence of FA was 26.3 ± 5.4 mm ( P < 0.05). FA stimulation of axon growth was reduced by an antibody that neutralized the activity of artemin ( P < 0.05). These data indicate that artemin is expressed in arteries, and its receptors are expressed and functional in the postganglionic sympathetic neurons that innervate them. This suggests that artemin may be a determinant of vascular sympathetic innervation.

Download Full-text

Role of nerve growth factor in the development of rat sympathetic neurons in vitro. III. Effect on acetylcholine production.

The Journal of Cell Biology ◽

10.1083/jcb.75.3.712 ◽

1977 ◽

Vol 75 (3) ◽

pp. 712-718 ◽

Cited By ~ 48

Author(s):

L L Chun ◽

P H Patterson

Keyword(s):

Nerve Growth Factor ◽

Growth Factor ◽

Rat Heart ◽

Neuronal Survival ◽

Sympathetic Neurons ◽

Cell Monolayer ◽

Heart Cell ◽

Heart Cells ◽

Nerve Growth ◽

Rat Heart Cells

The effect of nerve growth factor (NGF) on the development of cholinergic sympathetic neurons was studied in cultures grown either on monolayers of dissociated rat heart cells or in medium conditioned by them. In the presence of rat heart cells the absolute requirement of neurons for exogenous NGF was partially spared. The ability of heart cells to support neuronal survival was due at least in part to production of a diffusable NGF-like substance into the medium. Although some neurons survived on the heart cell monolayer without added NGF, increased levels of exogenous NGF increased neuronal survival until saturation was achieved at 0.5 microgram/ml 7S NGF. The ability of neurons to produce acetylcholine (ACh) from choline was also dependent on the level of exogenous NGF. In mixed neuron-heart cell cultures, NGF increased both ACh and catecholamine (CA) production per neuron to the same extent; saturation occurred at 1 microgram/ml 7S NGF. As cholinergic neurons developed in culture, they became less dependent on NGF for survival and ACh production, but even in older cultures approximately 40% of the neurons died when NGF was withdrawn. Thus, NGF is as necessary for survival, growth, and differentiation of sympathetic neurons when the neurons express cholinergic functions as when the neurons express adrenergic functions (4, 5).

Download Full-text

Regulation of Neuronal Survival and Axon Growth by a Perinuclear cAMP Compartment

Journal of Neuroscience ◽

10.1523/jneurosci.2752-18.2019 ◽

2019 ◽

Vol 39 (28) ◽

pp. 5466-5480 ◽

Cited By ~ 10

Author(s):

Tomasz Boczek ◽

Evan G. Cameron ◽

Wendou Yu ◽

Xin Xia ◽

Sahil H. Shah ◽

...

Keyword(s):

Neuronal Survival ◽

Axon Growth

Download Full-text

Neurotrophin-regulated signalling pathways

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2006.1894 ◽

2006 ◽

Vol 361 (1473) ◽

pp. 1545-1564 ◽

Cited By ~ 1199

Author(s):

Louis F Reichardt

Keyword(s):

Nervous System ◽

Map Kinases ◽

Sympathetic Neurons ◽

Axon Growth ◽

Synaptic Function ◽

Neurotrophin Receptor ◽

Signalling Pathways ◽

Tumour Necrosis Factor Receptor ◽

Trk Receptors ◽

Cell Fate Decisions

Neurotrophins are a family of closely related proteins that were identified initially as survival factors for sensory and sympathetic neurons, and have since been shown to control many aspects of survival, development and function of neurons in both the peripheral and the central nervous systems. Each of the four mammalian neurotrophins has been shown to activate one or more of the three members of the tropomyosin-related kinase (Trk) family of receptor tyrosine kinases (TrkA, TrkB and TrkC). In addition, each neurotrophin activates p75 neurotrophin receptor (p75NTR), a member of the tumour necrosis factor receptor superfamily. Through Trk receptors, neurotrophins activate Ras, phosphatidyl inositol-3 (PI3)-kinase, phospholipase C-γ1 and signalling pathways controlled through these proteins, such as the MAP kinases. Activation of p75NTR results in activation of the nuclear factor-κB (NF-κB) and Jun kinase as well as other signalling pathways. Limiting quantities of neurotrophins during development control the number of surviving neurons to ensure a match between neurons and the requirement for a suitable density of target innervation. The neurotrophins also regulate cell fate decisions, axon growth, dendrite growth and pruning and the expression of proteins, such as ion channels, transmitter biosynthetic enzymes and neuropeptide transmitters that are essential for normal neuronal function. Continued presence of the neurotrophins is required in the adult nervous system, where they control synaptic function and plasticity, and sustain neuronal survival, morphology and differentiation. They also have additional, subtler roles outside the nervous system. In recent years, three rare human genetic disorders, which result in deleterious effects on sensory perception, cognition and a variety of behaviours, have been shown to be attributable to mutations in brain-derived neurotrophic factor and two of the Trk receptors.

Download Full-text

The transport properties of axonal microtubules establish their polarity orientation.

The Journal of Cell Biology ◽

10.1083/jcb.120.6.1427 ◽

1993 ◽

Vol 120 (6) ◽

pp. 1427-1437 ◽

Cited By ~ 60

Author(s):

P W Baas ◽

F J Ahmad

Keyword(s):

Transport Properties ◽

Cell Body ◽

Sympathetic Neurons ◽

Neuronal Cell ◽

Axon Growth ◽

Progressive Increase ◽

Neuronal Cell Body ◽

Drug Concentrations ◽

Efficient Mechanisms ◽

Uniform Polarity

It is well established that axonal microtubules (MTs) are uniformly oriented with their plus ends distal to the neuronal cell body (Heidemann, S. R., J. M. Landers, and M. A. Hamborg. 1981. J. Cell Biol. 91:661-665). However, the mechanisms by which these MTs achieve their uniform polarity orientation are unknown. Current models for axon growth differ with regard to the contributions of MT assembly and transport to the organization and elaboration of the axonal MT array. Do the transport properties or assembly properties of axonal MTs determine their polarity orientation? To distinguish between these possibilities, we wished to study the initiation and outgrowth of axons under conditions that would arrest MT assembly while maintaining substantial levels of preexisting polymer in the cell body that could still be transported into the axon. We found that we could accomplish this by culturing rat sympathetic neurons in the presence of nanomolar levels of vinblastine. In concentrations of the drug up to and including 100 nM, the neurons actively extend axons. The vinblastine-axons are shorter than control axons, but clearly contain MTs. To quantify the effects of the drug on MT mass, we compared the levels of polymer throughout the cell bodies and axons of neurons cultured overnight in the presence of 0, 16, and 50 nM vinblastine with the levels of MT polymer in freshly plated neurons before axon outgrowth. Without drug, the total levels of polymer increase by roughly twofold. At 16 nM vinblastine, the levels of polymer are roughly equal to the levels in freshly plated neurons, while at 50 nM, the levels of polymer are reduced by about half this amount. Thus, 16 nM vinblastine acts as a "kinetic stabilizer" of MTs, while 50 nM results in some net MT disassembly. At both drug concentrations, there is a progressive increase in the levels of MT polymer in the axons as they grow, and a corresponding depletion of polymer from the cell body. These results indicate that highly efficient mechanisms exist in the neuron to transport preassembled MTs from the cell body into the axon. These mechanisms are active even at the expense of the cell body, and even under conditions that promote some MT disassembly in the neuron. MT polarity analyses indicate that the MTs within the vinblastine-axons, like those in control axons, are uniformly plus-end-distal.(ABSTRACT TRUNCATED AT 400 WORDS)

Download Full-text

T-type Ca 2+ channels are required for enhanced sympathetic axon growth by TNFα reverse signalling

Open Biology ◽

10.1098/rsob.160288 ◽

2017 ◽

Vol 7 (1) ◽

pp. 160288 ◽

Cited By ~ 9

Author(s):

Lilian Kisiswa ◽

Clara Erice ◽

Laurent Ferron ◽

Sean Wyatt ◽

Catarina Osório ◽

...

Keyword(s):

Sympathetic Neurons ◽

Sympathetic Innervation ◽

Axon Growth ◽

Tumour Necrosis Factor Receptor ◽

Kinase C ◽

Cultured Sympathetic Neurons ◽

Sympathetic Axon ◽

Pkc Activation ◽

Cell Somata ◽

Necrosis Factor

Tumour necrosis factor receptor 1 (TNFR1)-activated TNFα reverse signalling, in which membrane-integrated TNFα functions as a receptor for TNFR1, enhances axon growth from developing sympathetic neurons and plays a crucial role in establishing sympathetic innervation. Here, we have investigated the link between TNFα reverse signalling and axon growth in cultured sympathetic neurons. TNFR1-activated TNFα reverse signalling promotes Ca 2+ influx, and highly selective T-type Ca 2+ channel inhibitors, but not pharmacological inhibitors of L-type, N-type and P/Q-type Ca 2+ channels, prevented enhanced axon growth. T-type Ca 2+ channel-specific inhibitors eliminated Ca 2+ spikes promoted by TNFα reverse signalling in axons and prevented enhanced axon growth when applied locally to axons, but not when applied to cell somata. Blocking action potential generation did not affect the effect of TNFα reverse signalling on axon growth, suggesting that propagated action potentials are not required for enhanced axon growth. TNFα reverse signalling enhanced protein kinase C (PKC) activation, and pharmacological inhibition of PKC prevented the axon growth response. These results suggest that TNFα reverse signalling promotes opening of T-type Ca 2+ channels along sympathetic axons, which is required for enhanced axon growth.

Download Full-text