Overexpression of nerve growth factor in transgenic mice induces novel sympathetic projections to primary sensory neurons

Davis, Brian M.; Albers, Kathryn M.; Seroogy, Kim B.; Katz, David M.

doi:10.1002/cne.903490310

Cited by 85 publications

(42 citation statements)

References 63 publications

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“…This is consistent with the idea that NGF functions as a target-derived trophic factor capable of stimulating or modulating neuronal development, growth, and survival (41). It is also consistent with the findings from several different tissue-specific NGF transgenic mouse lines, in which NGF overexpression in pancreatic islets, pulmonary airways, skin, heart, brain, and smooth muscle resulted in the common phenotypic finding of increased sprouting by sympathetic efferent and sensory afferent nerve fibers to target organs and in many cases associated ganglion (2,20,27,28,36,37,39,45,46,104).…”

Section: Discussionsupporting

confidence: 81%

“…Anti-NGF treatment attenuated collateral sprouting into the DRG and pain-related behaviors in nerve injury-induced models of neuropathic pain (86). Transgenic mice overexpressing NGF in the skin (2,20,36) or glia (45,104) develop a similar pattern of sympathetic sprouting into target tissues and sensory ganglia, and GFAP-NGF mice showed enhanced thermal and mechanical hypersensitivity, as well as sympathetic sprouting following neuropathic nerve injury (87). Thermal hyperalgesia induced by intradermal NGF in the hindpaw was also partially dependent on sympathetic postganglionic axons (5).…”

Section: Discussionmentioning

confidence: 99%

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Overexpression of NGF in mouse urothelium leads to neuronal hyperinnervation, pelvic sensitivity, and changes in urinary bladder function

Schnegelsberg¹,

Sun

Cain

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

149

275

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Schnegelsberg B, Sun T, Cain G, Bhattacharya A, Nunn PA, Ford AP, Vizzard MA, Cockayne DA. Overexpression of NGF in mouse urothelium leads to neuronal hyperinnervation, pelvic sensitivity, and changes in urinary bladder function. Am J Physiol Regul Integr Comp Physiol 298: R534 -R547, 2010. First published December 23, 2009; doi:10.1152/ajpregu.00367.2009.-NGF has been suggested to play a role in urinary bladder dysfunction by mediating inflammation, as well as morphological and functional changes, in sensory and sympathetic neurons innervating the urinary bladder. To further explore the role of NGF in bladder sensory function, we generated a transgenic mouse model of chronic NGF overexpression in the bladder using the urothelium-specific uroplakin II (UPII) promoter. NGF mRNA and protein were expressed at higher levels in the bladders of NGF-overexpressing (NGF-OE) transgenic mice compared with wild-type littermate controls from postnatal day 7 through 12-16 wk of age. Overexpression of NGF led to urinary bladder enlargement characterized by marked nerve fiber hyperplasia in the submucosa and detrusor smooth muscle and elevated numbers of tissue mast cells. There was a marked increase in the density of CGRP-and substance P-positive C-fiber sensory afferents, neurofilament 200-positive myelinated sensory afferents, and tyrosine hydroxylase-positive sympathetic nerve fibers in the suburothelial nerve plexus. CGRP-positive ganglia were also present in the urinary bladders of transgenic mice. Transgenic mice had reduced urinary bladder capacity and an increase in the number and amplitude of nonvoiding bladder contractions under baseline conditions in conscious open-voiding cystometry. These changes in urinary bladder function were further associated with an increased referred somatic pelvic hypersensitivity. Thus, chronic urothelial NGF overexpression in transgenic mice leads to neuronal proliferation, focal increases in urinary bladder mast cells, increased urinary bladder reflex activity, and pelvic hypersensitivity. NGF-overexpressing mice may, therefore, provide a useful transgenic model for exploring the role of NGF in urinary bladder dysfunction. nerve growth factor; urothelium; transgenic mouse; bladder hypersensitivity; inflammation; afferent innervation NGF IS A POTENT NEUROTROPHIN that exerts pleiotropic effects in the peripheral and central nervous system. It regulates sensory and sympathetic neuronal development and maintenance (41) and plays a role in painful somatic and visceral inflammation (3,15,32,70,84,85). The effects of NGF are mediated through the TrkA and p75 NTR receptors and are tissue specific. It is well documented that NGF plays an important role in inflammation of the urinary bladder, colon, and lung (21,31,93,100). Although the contribution of NGF to urinary bladder function is unclear, it seems to play a role in urinary bladder hyperreflexia or overactivity (15,16,23,34,40,78,111). NGF administered intrathecally (107), intravesically (23), intramuscularly to the detrusor smooth muscle ...

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Overexpression of NGF in mouse urothelium leads to neuronal hyperinnervation, pelvic sensitivity, and changes in urinary bladder function

Schnegelsberg¹,

Sun

Cain

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

149

275

View full text Add to dashboard Cite

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“…The absence of staining could indicate a defect in axon arborization within target regions in the absence of TrkA. Data demonstrating hyperinnervation in tissues overexpressing NGF Albers et al, 1994;Davis et al, 1994) are consistent with this idea. However, our observation that cholinergic fiber density in the knock-out hippocampus at P20 -P25 appeared less than what was observed initially in knock-out animals at P7 argues for more than a defect in arborization.…”

Section: Role Of Trka In Cholinergic Process Outgrowth and Target Innsupporting

confidence: 52%

A Role for TrkA during Maturation of Striatal and Basal Forebrain Cholinergic NeuronsIn Vivo

et al. 1997

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Nerve growth factor (NGF), acting via the TrkA receptor, has been shown to regulate the survival and maturation of specific neurons of the peripheral nervous system. Furthermore, exogenous NGF has potent actions on TrkA-expressing cholinergic neurons of the basal forebrain (BFCNs) and striatum. However, initial analysis of mice lacking NGF or TrkA revealed that forebrain cholinergic neurons were present in these animals through the fourth postnatal week. Because of the potential effects of NGF/TrkA interactions on these developing neurons, we have analyzed quantitatively the striatal and basal forebrain cholinergic neurons in trkA knock-out mice. By postnatal day (P) 7/8, forebrain cholinergic neurons are smaller in trkA (Ϫ/Ϫ) mice than those in wild-type littermate controls. However, cholinergic neuron number and fiber density in the hippocampus, a target region of BFCNs, are grossly intact. Interestingly, by P20-P25 trkA knock-outs contain significantly fewer (20-36%) and smaller cholinergic neurons in both the striatum and septal regions, as compared with controls. Cholinergic fiber density within the hippocampus also is depleted in knock-outs by the end of the second postnatal week. Contrary to some predictions, despite expression of p75 NTR in the absence of trkA in BFCNs of these knock-out mice, many cells, although smaller, are still alive at P25. Our data suggest that, in the absence of NGF/TrkA signaling, striatal cholinergic neurons and BFCNs do not mature fully and that BFCNs begin to atrophy and/or die surrounding the time of target innervation.

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“…NGF alters the excitability and expression of transmitters/modulators in primary neurons (28,46). In addition, longer lasting increases in NGF expression may lead to sprouting of nerve terminals within the spinal cord, thereby potentially contributing to the changes in receptive field size, a mechanism unlikely to play a significant role in our findings considering the relatively short time course (12,47,49).…”

Section: Discussionmentioning

confidence: 88%

Convergence of sensory pathways in the development of somatic and visceral hypersensitivity

Bielefeldt¹,

Lamb²,

Gebhart³

2006

American Journal of Physiology-Gastrointestinal and Liver Physi

100

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Sensory neurons innervating different tissues converge onto second-order neurons in the spinal cord. We examined whether inflammation or transient overexpression of nerve growth factor (NGF) in one tissue triggers hypersensitivity in referral sites. Thresholds to mechanical and thermal stimulation of the hindpaw, visceromotor responses to colorectal distension, and cystometrograms were performed in appropriate controls and mice with experimentally induced cystitis, inflammation of the hindpaw or front paw, or injection of viral vectors encoding NGF or green fluorescent protein (GFP). Cystitis and NGF but not GFP overexpression in the bladder triggered bladder hyperactivity associated with mechanical and thermal hypersensitivity in cutaneous referral sites and enhanced responses to colorectal distension. Hindpaw inflammation and injection of the NGF- but not GFP-encoding viral vector or front paw inflammation induced mechanical and thermal hyperalgesia in the affected hindpaw and increased responses to colorectal distension without altering the micturition reflex. In conclusion, sensitization of sensory pathways by inflammation or NGF contributes to the development of hypersensitivity in neighboring organs and cutaneous referral sites and provides a potential mechanism underlying the coexistence of pain syndromes in patients with functional diseases.

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Overexpression of nerve growth factor in transgenic mice induces novel sympathetic projections to primary sensory neurons

Cited by 85 publications

References 63 publications

Overexpression of NGF in mouse urothelium leads to neuronal hyperinnervation, pelvic sensitivity, and changes in urinary bladder function

Overexpression of NGF in mouse urothelium leads to neuronal hyperinnervation, pelvic sensitivity, and changes in urinary bladder function

A Role for TrkA during Maturation of Striatal and Basal Forebrain Cholinergic NeuronsIn Vivo

Convergence of sensory pathways in the development of somatic and visceral hypersensitivity

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