The regulation of nerve growth factor synthesis and delivery to peripheral neurons

doi:10.1016/0163-7258(94)00059-C

Pharmacology & Therapeutics

Volume 65, Issue 1, 1995, Pages 93-123

https://doi.org/10.1016/0163-7258(94)00059-C Get rights and content

Abstract

Recent experiments have provided new insights into the way in which the synthesis of nerve growth factor (NGF) is regulated. In particular, a variety of agents have been found to influence the cellular concentration of mRNA^NGF and NGF both in vitro and in vivo. However, no clear mechanism has been found to indicate the existence of a feedback regulation of NGF synthesis by effector tissue innervation. We have argued in this review that some form of feedback control is likely to exist between the innervation and the cells producing the factor. One such possibility, the regulation of the availability of NGF by control of its secretion, is discussed.

References (296)

I.K. Abrahamson et al.
Endogenous chicken nerve growth factor from sheath cells is transported in regenerating nerve
Dev. Biol.
(1987)
A. Acheson et al.
High K⁺-mediated survival of spinal sensory neurons depends on developmental stage
Exp. Cell Res.
(1987)
R.F. Alderson et al.
Brain-derived neurotrophic factor increases survival and differentiated functions of rat septal cholinergic neurons in culture
Neuron
(1990)
J.M. Alexander et al.
Cell-specific and developmental regulation of a nerve growth factor-human growth hormone fusion gene in transgenic mice
Neuron
(1989)
C.A. Altar et al.
Receptor-mediated transport of human recombinant nerve growth factor from olfactory bulb to forebrain cholinergic nuclei
Brain Res.
(1991)
G. Auburger et al.
Developmental changes of nerve growth factor and its mRNA in the rat hippocampus: comparison with choline acetyltransferase
Dev. Biol.
(1987)
M. Ballarin et al.
Hippocampal damage and kainic acid injection induce a rapid increase in mRNA for BDNF and NGF in the rat brain
Exp. Neurol.
(1991)
Y.A. Barde
Trophic factors and neuronal survival
Neuron
(1989)
R.T. Bartus et al.
Neuropeptide effects on memory in aged monkeys
Neurobiol. Aging
(1982)
L.R. Berkemeier et al.
Neurotrophin-5: a novel neurotrophic factor that activates trk and trkB
Neuron
(1991)

R.B. Campenot

Development of sympathetic neurons in compartmentalized cultures. IL control of neurite growth by nerve growth factor

Dev. Biol.

(1982)

D.O. Clegg et al.

Regulation of nerve growth factor mRNA levels in developing rat heart ventricle is not altered by sympathectomy

Dev. Biol.

(1989)

A. Davies et al.

Influence of NGF on developing dorso-medial and ventro-lateral neurons of chick and mouse trigeminal ganglia

Int. J. Devl Neurosci.

(1983)

S.R. D'Mello et al.

Structural and functional identification of regulatory regions and cis elements surrounding the nerve growth factor gene promoter

Molec. Brain Res.

(1991)

R.H. Edwards

Regulation of nerve growth factor expression

R.H. Edwards et al.

Processing of the native nerve growth factor precursor to form biologically active nerve growth factor

J. biol. Chem.

(1988)

R.H. Edwards et al.

Directed expression of NGF to pancreatic β-cells in transgenic mice leads to selective hyperinnervation of the islets

Cell

(1989)

P. Ernfors et al.

Increased levels of messenger RNAs for neurotrophic factors in the brain during kindling epileptogenesis

Neuron

(1991)

R.N. Fabricant et al.

Increased levels of nerve-growth-factor cross-reacting protein in ‘central’ neurofibromatosis

Lancet

(1979)

J.L. Franklin et al.

Suppression of programmed neuronal death by sustained elevation of cytoplasmic calcium

TINS

(1992)

Y. Furukawa et al.

Catecholamines induce and increase in nerve growth factor content in the medium of mouse L-M cells

J. biol. Chem.

(1986)

Y. Furukawa et al.

Aliphatic side chain of catecholamine potentiates the stimulatory effect of the catechol part on the synthesis of nerve growth factor

FEBS Lett.

(1986)

Y. Furukawa et al.

Stimulatory effect of 4-alkylcatechols and their diacetylated derivatives on the synthesis of nerve growth factor

Biochem. Pharmac.

(1990)

R.A. Gadient et al.

Interleukin-1 and tumor necrosis factor-alpha synergystically stimulate nerve growth factor (NGF) release from cultured rat astrocytes

Neurosci. Lett.

(1990)

C. Gall et al.

Kainic acid-induced seizures stimulate increased expression of nerve growth factor mRNA in rat hippocampus

Molec. Brain Res.

(1991)

H. Gnahn et al.

NGF-mediated increase of choline acetyltransferase (ChAT) in the neonatal rat forebrain evidence for a physiological role of NGF in the brain?

Dev. Brain Res.

(1983)

M. Goedert et al.

Biochemical effects of antibodies against nerve growth factor on developing and differentiated sympathetic ganglia

Brain Res.

(1978)

M. Goedert et al.

Nerve growth factor mRNA in peripheral and central rat tissues and in human central nervous system: lesion effects in the rat brain and levels in Alzheimer's disease

Molec. Brain Res.

(1986)

D. Gonzalez et al.

Expression of beta-nerve growth factor in cultured cells derived from the hypothalamus and cerebral cortex

Brain Res.

(1990)

L.A. Greene

Quantitative in vitro studies on the nerve growth factor (NGF) requirement of neurons: sensory neurons

Dev. Biol.

(1977)

L.A. Greene

Quantitative in vitro studies on the nerve growth factor (NGF) requirements of neurons: sympathetic neurons

Dev. Biol.

(1977)

B.J. Gwag et al.

Regulation of nerve growth factor mRNA in the hippocampal formation: effects of $N- methyl- d -aspartate$ receptor activation

Exp. Neurol.

(1993)

T. Hagg et al.

Delayed treatment with nerve growth factor reverses the apparent loss of cholinergic neurons after acute brain damage

Exp. Neurol.

(1988)

T. Hagg et al.

Nerve growth factor (NGF) reverses axotomy-induced decreases in choline acetyltransferase, NGF receptor and size of medial septum cholinergic neurons

Brain Res.

(1989)

F. Hallböök et al.

Evolutionary studies of the nerve growth factor family reveal a novel member abundantly expressed in Xenopus ovary

Neuron

(1991)

I.E. Akerblom et al.

Negative regulation by glucocorticoids through interference with a cAMP responsive enhancer

Science

(1988)

J.D. Allen et al.

Novel murine homeo box gene on chromosome 1 expressed in specific hematopoietic lineages and during embryogenesis

Genes Devl

(1991)

L. Aloe

Adrenalectomy decreases nerve growth factor in young adult rat hippocampus

L. Aloe et al.

Light and electron microscopic studies on the excessive growth of sympathetic ganglia in rats injected daily from birth with 6-OHDA and NGF

Archs ital. Biol.

(1975)

L. Aloe et al.

Aggressive behaviour induces release of nerve growth factor from mouse salivary gland in the bloodstream

L. Aloe et al.

Nerve growth factor in the synovial fluid of patients with chronic arthritis

Arthritis Rheumatism

(1992)

R.H. Angeletti et al.

Amino acid sequences of 2.5S nerve growth factor. II. Isolation and characterization of the thermolytic and peptic peptides and the complete structure

Biochemistry

(1973)

S.C. Apfel et al.

Nerve growth factor prevents toxic neuropathy in mice

Ann. Neurol.

(1991)

S.C. Apfel et al.

Nerve growth factor prevents experimental cisplatin neuropathy

Ann. Neurol.

(1992)

H. Awatsuji et al.

Interleukin-4 and -5 as modulators of nerve growth factor synthesis-secretion in astrocytes

J. Neurosci. Res.

(1993)

T.L. Babb

Bilateral pathological damage in temporal lobe epilepsy

Can. J. neurol. Sci.

(1991)

C.E. Bandtlow et al.

Cellular localization of nerve growth factor synthesis by in situ hybridization

EMBO J.

(1987)

I. Barakat-Walter et al.

Changes in nuclear 3,5,3′-triiodothyronine receptor expression in rat dorsal root ganglia and sciatic nerve during development: comparison with regeneration

Eur. J. Neurosci.

(1993)

G. Barbany et al.

Regulation of neurotrophin mRNA expression in the rat brain by glucocorticoids

Eur. J. Neurosci.

(1992)

Y.A. Barde et al.

Purification of a new neurotrophic factor from mammalian brain

EMBO J.

(1982)

Cited by (29)

Post-injury regeneration in rat sciatic nerve facilitated by neurotrophic factors secreted by amniotic fluid mesenchymal stem cells
2007, Journal of Clinical Neuroscience
Citation Excerpt :
Neurotrophic factors, soluble substances produced by a peripheral target structure, are taken up by axons and then transported through retrograde axonal flow to the nerve cell body, where they exert trophic effects.29 Some factors, including members of the neurotrophic family such as CNTF and NT-3, have been investigated for their ability to enhance the regenerative capacity of nerve tissue.14,30 CNTF is expressed by Schwann cells of the peripheral nervous system and astrocytes of the CNS.31
Amniotic fluid mesenchymal stem cells have the ability to secrete neurotrophic factors that are able to promote neuron survival in vitro. The purpose of this study was to evaluate the effects of neurotrophic factors secreted by rat amniotic fluid mesenchymal stem cells on regeneration of sciatic nerve after crush injury. Fifty Sprague–Dawley rats weighing 250–300 g were used. The left sciatic nerve was crushed with a vessel clamp. Rat amniotic fluid mesenchymal stem cells embedded in fibrin glue were delivered to the injured nerve. Enzyme-linked immunosorbent assay (ELISA) and immunocytochemistry were used to detect neurotrophic factors secreted by the amniotic fluid mesenchymal stem cells. Nerve regeneration was assessed by motor function, electrophysiology, histology, and immunocytochemistry studies. Positive CD29/44, and negative CD11b/45, as well as high levels of expression of brain-derived neurotrophic factor, glia cell line-derived neurotrophic factor, ciliary neurotrophic factor (CNTF), nerve growth factor, and neurotrophin-3 (NT-3) were demonstrated in amniotic fluid mesenchymal stem cells. Motor function recovery, the compound muscle action potential, and nerve conduction latency showed significant improvement in rats treated with amniotic fluid mesenchymal stem cells. ELISA measurement in retrieved nerves displayed statistically significant elevation of CNTF and NT-3. The immunocytochemical studies demonstrated positive staining for NT-3 and CNTF in transplanted cells. The histology and immunocytochemistry studies revealed less fibrosis and a high level of expression of S-100 and glial fibrillary acid protein at the crush site. Rat amniotic fluid mesenchymal stem cells may facilitate regeneration in the sciatic nerve after crush injury. The increased nerve regeneration found in this study may be due to the neurotrophic factors secreted by amniotic fluid mesenchymal stem cells.
Responsiveness of sympathetic and sensory iridial nerves to NGF treatment in young and aged rats
2001, Neurobiology of Aging
Altered neuronal responses to trophic factors may play a role in neuronal maintenance in adulthood and may also be involved in neuronal atrophy in old age. We have investigated this issue in the rat iris, studying responsiveness of sympathetic and sensory iridial nerves to a range of NGF concentrations in mature and aged rats. We show here that growth responses of sensory nerves to NGF, as measured by quantitative immunohistochemistry and image analysis, were unchanged in old rats. In contrast, there was a small but significant reduction in responsiveness of aged sympathetic neurons. The shapes of the dose-response curves for sensory and sympathetic neurons were different, with a larger response over a narrower range of concentrations in sensory neurons. Lower levels of p75 immunoreactivity were observed in iridial nerves from old compared to young rats. NGF treatment had no effect on receptor staining in young rats but restored ‘young’ levels of p75 staining in old rats. Our results do not support the hypothesis of a primary role for NGF in maintenance or atrophy of nerves in ageing.
Neuroprotection mediated via neurotrophic factors and induction of neurotrophic factors
1999, Brain Research Reviews
Neurotrophins and other neurotrophic factors have been shown to support the survival and differentiation of many neuronal populations of the central and peripheral nervous system. Therefore, administering neurotrophic factors could represent an alternative strategy for the treatment of acute and chronic brain disorders. However, the delivery of neurotrophic factors to the brain is one of the largest obstacles in the development of effective therapy for neurodegenerative disorders, because these proteins are not able to cross the blood–brain barrier. The induction of growth factor synthesis in the brain tissue by systemically administered lipophilic drugs, such as β-adrenoceptor agonists, shown to increase endogenous nerve growth factor (NGF) synthesis in the brain, would be an elegant way to overcome these problems of application. Stimulation of β-adrenoceptors with clenbuterol led to increased NGF synthesis in cultured central nervous system (CNS) cells and rat brain tissue. Clenbuterol-induced NGF expression was reduced to the control levels by coadministration of β-adrenoceptor antagonist propranolol. Furthermore, clenbuterol protected rat hippocampal neurons subjected to excitotoxic damage. The neuroprotective effect of clenbuterol in vitro depended on increased NGF synthesis, since the neuroprotection was abolished by NGF antisense oligonucleotide as well as by antibodies directed against NGF itself. In vivo, clenbuterol protected rat hippocampus in a model of transient forebrain ischemia and reduced the infarct volume in a rat model of permanent middle cerebral artery occlusion (MCAo). The neuroprotective effect of clenbuterol in vivo was accompanied by enhanced NGF synthesis in brain tissue. These findings support our hypothesis that orally active NGF inducers may have a potential as therapeutic agents for the treatment of neurodegenerative disorders and stroke.
NGF depletion reduces ipsilateral and contralateral trigeminal satellite cell reactions after inferior alveolar nerve injury in adult rats
1998, Experimental Neurology
Following peripheral nerve injury, neuronal cell functions in sensory ganglia shift from normal maintenance and neurotransmission toward survival and regeneration. A rapid modulation of glial cell activity, which is related to changes in neuronal-support cell interaction, also occurs after nerve injury. Nerve growth factor (NGF) is required for the survival and maintenance of specific populations of sensory and sympathetic neurons, and changes in neuronal gene expression after axonal injury are due in part to a loss of NGF retrograde transport from the periphery to the cell body. A similar role for NGF in modulating support cell responses to peripheral nerve injury, however, has not been demonstrated. Using an autoimmune model, we assessed the effects of NGF depletion in adult rats on the injury-induced expression of glial fibrillary acid protein immunoreactivity (GFAP-IR) in the ipsilateral and contralateral trigeminal ganglia (TG). Unilateral inferior alveolar nerve crush resulted in abilateral,NGF-dependent trigeminal satellite cell response. In control rats there was a widespread induction of GFAP-IR in the ipsilateral as well as the contralateral TG. In contrast, GFAP-IR was reduced to the mandibular division of the ipsilateral TG in NGF-depleted rats, and the contralateral up-regulation of GFAP-IR was entirely abolished. Bilateral sympathectomy failed to mimic the effects of autoimmunization. Our results provide evidence that NGF depletion inhibits injury-induced satellite cell responses, independent of its effects on sympathetic nerve function.
Partial cortical devascularization results in elevations of cortical nerve growth factor and increases nerve growth factor protein within basal forebrain cholinergic neurons
1998, Neuroscience
Previous studies have demonstrated that partial cortical devascularization results in increased levels of nerve growth factor protein within the tissue immediately surrounding the infarcted region. In the present study, we have used this lesion model to further characterize the nerve growth factor increase by investigating: (i) the time course for this phenomenon; (ii) the impact of the devascularizing lesion on cortical regions not directly impinged upon by the lesion; and (iii) the response of nerve growth factor-sensitive nucleus basalis neurons providing afferent cortical innervation to the increased availability of nerve growth factor within their target territory. Our results indicate that, within the infarcted cortex, nerve growth factor levels increase rapidly following the lesion (up 51% by one day post lesion), reach a maximum of 136% above controls by three days and undergo a slow decline back to baseline levels by 23 days. Within the frontal and cingulate cortices, which are not devascularized by the lesion and show no signs of pathological damage, nerve growth factor levels increase over a similar time course, and with a similar magnitude, to those in the lesioned cortex. Nerve growth factor-sensitive nucleus basalis neurons on the side ipsilateral to the lesion respond to increased cortical nerve growth factor levels with an increased accumulation of nerve growth factor within their cell bodies (revealed by nerve growth factor immunohistochemistry and quantitative enzyme-linked immunosorbent assay) which was apparent at three days following the lesion, but no longer discernible at seven or 14 days or later.
The present study investigated a model of cortical devascularization for its ability to alter nerve growth factor levels within the cortex. Nerve growth factor levels were rapidly increased within the infarcted cortical tissue beneath the lesion but were also elevated to a similar extent, and with a similar time course, in cortical regions not directly impinged upon by the lesion. The retrograde impact of elevated cortical nerve growth factor levels was demonstrated by an increased accumulation of nerve growth factor within the cell bodies of nucleus basalis neurons providing innervation to the cortex. This lesion model should provide a potential avenue for investigating the functional role(s) of nerve growth factor in the intact and lesioned adult central nervous system, as well as the internal mechanisms for regulating its synthesis, release, uptake, and degradation.
Plasticity in adult and ageing sympathetic neurons
1998, Progress in Neurobiology
The nature of neural plasticity and the factors that influence it vary throughout life. Adult neurons undergo extensive and continual adaptation in response to demands that are quite different from those of early development. We review the main influences on the survival, growth and neurotransmitter expression in adult and ageing sympathetic neurons, comparing these influences to those at work in early development. This “developmental” approach is proposed because, despite the contrasting needs of different phases of development, each phase has a profound infuence on the mechanisms of plasticity available to its successors. Interactions between neurons and their targets, whether effector cells or other neurons, are vital to all of these aspects of neural plasticity.
Sympathetic neurons require access to target-derived diffusible neurotrophic factors such as NGF, NT3 and GDNF, as well as to bound elements of the extracellular matrix such as laminin. These factors probably influence plasticity throughout life. In adult life, and even in old age, sympathetic neurons are relatively resistant to cell death. However, they continue to require target-derived diffusible and bound factors for their maintenance, growth and neurotransmitter expression. Failure to maintain appropriate neuronal function in old age, for example in the breakdown of homeostasis, may result partly from a disturbance of the dynamic, trophic relationship between neurons and their targets. However, there is no clear evidence that this is due to a failure of targets to synthesize neurotrophic factors.
On the neural side of the equation, altered responsiveness of sympathetic neurons to neurotrophic factors suggests that expression of the trk and p75 neurotrophin receptors contributes to neuronal survival, maintenance and growth in adulthood and old age. Altered receptor expression may therefore underlie the selective vulnerability of some sympathetic neurons in old age. The role of neural connectivity and activity in the regulation of synthesis of target-derived factors, as well as in neurotransmitter dynamics, is reviewed.

View all citing articles on Scopus

View full text

The regulation of nerve growth factor synthesis and delivery to peripheral neurons

Abstract

Dev. Biol.

Exp. Cell Res.

Neuron

Neuron

Brain Res.

Dev. Biol.

Exp. Neurol.

Neuron

Neurobiol. Aging

Neuron

Dev. Biol.

Dev. Biol.

Int. J. Devl Neurosci.

Molec. Brain Res.

J. biol. Chem.

Cell

Neuron

Lancet

TINS

J. biol. Chem.

FEBS Lett.

Biochem. Pharmac.

Neurosci. Lett.

Molec. Brain Res.

Dev. Brain Res.

Brain Res.

Molec. Brain Res.

Brain Res.

Dev. Biol.

Dev. Biol.

Exp. Neurol.

Exp. Neurol.

Brain Res.

Neuron

Negative regulation by glucocorticoids through interference with a cAMP responsive enhancer

Science

Novel murine homeo box gene on chromosome 1 expressed in specific hematopoietic lineages and during embryogenesis

Genes Devl

Adrenalectomy decreases nerve growth factor in young adult rat hippocampus

Light and electron microscopic studies on the excessive growth of sympathetic ganglia in rats injected daily from birth with 6-OHDA and NGF

Archs ital. Biol.

Aggressive behaviour induces release of nerve growth factor from mouse salivary gland in the bloodstream

Nerve growth factor in the synovial fluid of patients with chronic arthritis

Arthritis Rheumatism

Amino acid sequences of 2.5S nerve growth factor. II. Isolation and characterization of the thermolytic and peptic peptides and the complete structure

Biochemistry

Nerve growth factor prevents toxic neuropathy in mice

Ann. Neurol.

Nerve growth factor prevents experimental cisplatin neuropathy

Ann. Neurol.

Interleukin-4 and -5 as modulators of nerve growth factor synthesis-secretion in astrocytes

J. Neurosci. Res.

Bilateral pathological damage in temporal lobe epilepsy

Can. J. neurol. Sci.

Cellular localization of nerve growth factor synthesis by in situ hybridization

EMBO J.

Changes in nuclear 3,5,3′-triiodothyronine receptor expression in rat dorsal root ganglia and sciatic nerve during development: comparison with regeneration

Eur. J. Neurosci.

Regulation of neurotrophin mRNA expression in the rat brain by glucocorticoids

Eur. J. Neurosci.

Purification of a new neurotrophic factor from mammalian brain

EMBO J.