The nerve growth factor precursor proNGF exhibits neurotrophic activity but is less active than mature nerve growth factor

Fahnestock, Margaret; Yu, Guopan; Michalski, Bernadeta; Mathew, Silvy; Colquhoun, Amy; Ross, Gregory M.; Coughlin, Michael D.

doi:10.1111/j.1471-4159.2004.02360.x

Cited by 159 publications

(186 citation statements)

References 52 publications

(123 reference statements)

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“…However, there is some controversy regarding the prosurvival role of proNGF in the brain. High proNGF concentrations can stimulate PC12 cell survival when the p75NTR/TrkA ratio is low (Fahnestock et al 2004). It was established that the receptors balance, i.e., the relative level of Trk and p75NTR, is a crucial determinant of cell fate during development and that it is required for further modulation of neurite outgrowth/synaptic plasticity in the adult brain (Masoudi et al 2009).…”

Section: Discussionmentioning

confidence: 99%

BDNF transcripts, proBDNF and proNGF, in the cortex and hippocampus throughout the life span of the rat

Perović

Tešić

Djordjevic

et al. 2012

AGE

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Neurotrophins are established molecular mediators of neuronal plasticity in the adult brain. We analyzed the impact of aging on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) protein isoforms, their receptors, and on the expression patterns of multiple 5′ exon-specific BDNF transcripts in the rat cortex and hippocampus throughout the life span of the rat (6, 12, 18, and 24 months of age). ProNGF was increased during aging in both structures. Mature NGF gradually decreased in the cortex, and, in 24-month-old animals, it was 30 % lower than that in adult 6-month-old rats. The BDNF expression did not change during aging, while proBDNF accumulated in the hippocampus of aged rats. Hippocampal total BDNF mRNA was lower in 12-month-old animals, mostly as a result of a decrease of BDNF transcripts 1 and 2. In contrast to the regionspecific regulation of specific exon-containing BDNF mRNAs in adult animals, the same BDNF RNA isoforms (containing exons III, IV, or VI) were present in both brain structures of aged animals. Deficits in neurotrophin signaling were supported by the observed decrease in Trk receptor expression which was accompanied by lower levels of the two main downstream effector kinases, pAkt and protein kinase C. The proteolytic processing of p75NTR observed in 12-monthold rats points to an additional regulatory mechanism in early aging. The changes described herein could contribute to reduced brain plasticity underlying the age-dependent decline in cognitive function.

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Section: Discussionmentioning

confidence: 99%

BDNF transcripts, proBDNF and proNGF, in the cortex and hippocampus throughout the life span of the rat

Perović

Tešić

Djordjevic

et al. 2012

AGE

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“…Taken together, these findings suggest that high MW NGF species are abundant in the nervous system and may have their own biological activity. Some have suggested an apoptotic role for proNGF (Lee et al 2001;Beattie et al 2002;Harrington et al 2004;Pedraza et al 2005), though proNGF also has been shown to have neurotrophic activities Reinshagen et al 2000;Fahnestock et al 2004).…”

Section: Function Of Ngf and Nt-3 Protein Speciesmentioning

confidence: 99%

Regulation of NGF and NT-3 protein expression in peripheral targets by sympathetic input

2007

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Nerve growth factor (NGF) and neurotrophin-3 (NT-3) are target-derived proteins that regulate innervating sympathetic neurons. Here, we used western blot analysis to investigate changes in NGF and NT-3 protein in several peripheral tissues following loss of sympathetic input. Following removal of the superior cervical ganglion (SCG), large molecular weight (MW) NGF species, including proNGF-A, were increased in distal intracranial SCG targets, such as pineal gland and extracerebral blood vessels (bv). Mature NGF was a minor species in these tissues and unchanged following sympathectomy. Large MW NGF species also were increased when sympathectomy was followed by in vivo NGF administration. Mature NT-3, which was abundant in controls, was significantly decreased in these targets following sympathetic denervation. The decrease in mature NT-3 was enhanced following NGF administration. The trigeminal ganglion, which provides sensory input to these targets, showed increased NGF, but decreased NT-3, in these treatments, demonstrating that decreased NT-3 at the targets did not result from enhanced NT-3 uptake. Unlike pineal gland and extracerebral bv, the external carotid artery, an extracranial proximal SCG target, showed no change in NGF following denervation, and mature NT-3 was significantly increased. Following NGF administration, NT-3 was significantly decreased. We provide evidence for sympathetic regulation of NGF and NT-3 in peripheral targets and that elevated NGF can depress NT-3. The differential response in distal and proximal adult targets is consistent with the idea that neurons innervating proximal and distal targets may serve different roles in regulating neurotrophin protein. In addition, we conclude that previous ELISA results showing increased NGF protein following sympathetic denervation may have resulted from increases in large MW species, rather than an increase in mature NGF.

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“…Among the NTs, nerve growth factor (NGF) plays a pivotal role in the control of the differentiation and survival of peripheral sympathetic and sensory nerve fibres as well as the functionality of cholinergic neurons (Lindsay et al 1994, Aloe et al 2012. The mature NGF molecule results from the proteolysis of a precursor form (proNGF), which is also bioactive and exerts both pro-apoptotic and neurotrophic effects during development and adult life (Fahnestock et al 2001(Fahnestock et al , 2004. Both forms exert their biological activities upon ligation of the specific tropomyosin kinase receptor A (TRKA), which is a typical tyrosine kinase receptor (Huang & Reichardt 2003), as well as of the low-affinity and non-selective p75 pan-NT receptor (p75NTR).…”

Section: Introductionmentioning

confidence: 99%

Balanced levels of nerve growth factor are required for normal pregnancy progression

Frank¹,

Barrientos²,

Tirado‐González³

et al. 2014

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Nerve growth factor (NGF), the first identified member of the family of neurotrophins, is thought to play a critical role in the initiation of the decidual response in stress-challenged pregnant mice. However, the contribution of this pathway to physiological events during the establishment and maintenance of pregnancy remains largely elusive. Using NGF depletion and supplementation strategies alternatively, in this study, we demonstrated that a successful pregnancy is sensitive to disturbances in NGF levels in mice. Treatment with NGF further boosted fetal loss rates in the high-abortion rate CBA/J x DBA/2J mouse model by amplifying a local inflammatory response through recruitment of NGF-expressing immune cells, increased decidual innervation with substance P C nerve fibres and a Th1 cytokine shift. Similarly, treatment with a NGF-neutralising antibody in BALB/c-mated CBA/J mice, a normal-pregnancy model, also induced abortions associated with increased infiltration of tropomyosin kinase receptor A-expressing NK cells to the decidua. Importantly, in neither of the models, pregnancy loss was associated with defective ovarian function, angiogenesis or placental development. We further demonstrated that spontaneous abortion in humans is associated with up-regulated synthesis and an aberrant distribution of NGF in placental tissue. Thus, a local threshold of NGF expression seems to be necessary to ensure maternal tolerance in healthy pregnancies, but when surpassed may result in fetal rejection due to exacerbated inflammation.

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The nerve growth factor precursor proNGF exhibits neurotrophic activity but is less active than mature nerve growth factor

Cited by 159 publications

References 52 publications

BDNF transcripts, proBDNF and proNGF, in the cortex and hippocampus throughout the life span of the rat

BDNF transcripts, proBDNF and proNGF, in the cortex and hippocampus throughout the life span of the rat

Regulation of NGF and NT-3 protein expression in peripheral targets by sympathetic input

Balanced levels of nerve growth factor are required for normal pregnancy progression

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