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Query: UNIPROT:Q9UIJ5 (Rec)
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Increasing evidence suggests that, in addition to peripheral sensory and sympathetic neurons, the enteric neurons are also under the control of neurotrophins. Recently, neurotrophin receptors have been detected in the developing and adult mammalian enteric nervous system (ENS). Nevertheless, it remains to be established whether neurotrophin receptors are expressed in all enteric neurons and/or in glial cells and whether expression is a common feature in the enteric nervous system of all mammals or if interspecific differences exist. Rabbit polyclonal antibodies against Trk proteins (regarded as essential constituents of the high-affinity signal-transducing neurotrophin receptors) and p75 protein (considered as a low-affinity pan-neurotrophin receptor) were used to investigate the cell localization of these proteins in the ENS of adult man, horse, cow, sheep, pig, rabbit, and rat. Moreover, the percentage of neurons displaying immunoreactivity (IR) for each neurotrophin receptor protein was determined. TrkA-like IR and TrkC-like IR were observed in a neuronal subpopulation in both the myenteric and submucous plexuses, from esophagus to rectum in humans, and in the jejunum-ileum of the other species. Many neurons, and apparently all glial cells, in the human and rat enteric nervous system also displayed p75 IR. TrkB-like IR was found restricted to the glial cells of all species studied, with the exception of humans, in whom IR was mainly in glial cells and a small percentage of enteric neurons (about 5%). These findings indicate that the ENS of adult mammals express neuronal TrkA and TrkC, glial TrkB, and neuronal-glial p75, this pattern of distribution being similar in all examined species. Thus, influence of specific neurotrophins on their cognate receptors may be considered in the physiology and/or pathology of the adult ENS.
Anat Rec 1998 07
PMID:A neuronal subpopulation in the mammalian enteric nervous system expresses TrkA and TrkC neurotrophin receptor-like proteins. 966 64

Human skin, including nerves and sensory corpuscles, displays immunoreactivity (IR) for low- (p75) and high-affinity (TrkA-like) receptors for nerve growth factor (NGF), the best characterized member of the family of neurotrophins. This study was designed to analyze the changes induced by spinal cord and peripheral nerve injuries in the expression of neurotrophin receptors in digital skin, with special reference to nerves and sensory corpuscles. Skin biopsy samples were obtained from 1) the hand and toes of normal subjects, 2) below the level of the lesion of patients with spinal cord injury affecting dorsal and lateral funiculi, 3) the cutaneous territory of entrapped peripheral nerves (median and ulnar nerves), and 4) the cutaneous territory of sectioned and grafted nerves (median nerve). The pieces were formalin-fixed and paraffin-embedded, cut in serial sections, and processed for immunohistochemistry using antibodies against human p75 and TrkA proteins. The percentage of sensory corpuscles displaying IR for p75 and TrkA-like, as well as the intensity of IR developed within them, was assessed using quantitative image analysis. Spinal cord severance causes a decrease in p75 IR in Meissner and Pacinian corpuscles, whereas TrkA-like IR did not vary. In other nonnervous tissues (i.e., epidermis, sweat glands), both p75 and TrkA-like IR was diminished or even absent. Similar but more severe changes were encountered in the skin from the territory of entrapped nerves. Finally, in subjects with sectioned-grafted nerves, p75 IR was found close to controls in nerves, reduced in Meissner corpuscles, and absent in the inner core of the Pacinian ones; TrkA-like IR was in the perineurium, a small percentage of Meissner corpuscles (about 7%), and the outer core and capsule of the Pacinan corpuscles. In the nonnervous tissues, p75 IR was practically absent, whereas TrkA-like IR did not change. No changes in the expression of neurotrophin receptors were observed in Merkel cells of the different groups. Present results show the following: 1) expression of nerve p75 IR in human cutaneous sensory corpuscles is sensitive to central deafferentation, to blockade or difficulty in axonal transport, and to disruption of axonal continuity independently of possible restoration of axonal integrity due to grafts; 2) expression of TrkA-like IR in nerves and sensory corpuscles is sensitive only to nerve transection; 3) the corpuscular Schwann-related cells are the only cells involved in the above modifications, the perineurial cells remaining unchanged; 4) the expression of p75 and TrkA-like IR by Merkel cells is independent of normal innervation; 5) an adequate innervation of the skin seems to be necessary for the expression of p75 but not TrkA-like in nonneuronal cells, especially in the epidermis. A role for NGF in the maintenance of epidermis integrity is discussed.
Anat Rec 1998 07
PMID:p75 and TrkA neurotrophin receptors in human skin after spinal cord and peripheral nerve injury, with special reference to sensory corpuscles. 966 65

The low-affinity neurotrophin receptor (p75) binds all members of the neurotrophin family. In the rat, during the first week postpartum, dense p75-immunoreactivity (IR) is present throughout all components of the trigeminal brainstem complex (TBC), largely associated with primary sensory afferents. Within subnucleus caudalis (SpC) of the TBC, intense p75-IR is present in all laminae at birth. During the second and third postnatal weeks, p75-IR in SpC gradually fades within the deeper laminae, becoming generally restricted in the adult to laminae I and II. Similar declines in p75-IR intensity occur in the subnucleus oralis (SpO); in the SpO in the adult, p75-IR is confined to the dorsalmost portion of SpO. In subnucleus interpolaris, an emerging, vibrissa-related pattern of p75-IR is detectable on PD0 (first 24 hr postpartum), which becomes fully differentiated during PD4-PD7. However, this pattern gradually disappears during the third postnatal week. Ventrally in the nucleus principalis (PrV), a pattern of p75-IR that mirrors the topographical arrangement of the vibrissae is detectable by PD0-PD1, is fully differentiated by the end of the first postnatal week, and persists into adulthood. Perinatal unilateral sectioning of the infraorbital nerve on PD0-PD1, but not as late as PD4, disrupts p75-IR patterning in the adult PrV. Although p75 appears to be associated with primary afferent pattern formation, to determine whether it is essential, we examined mutant mice unable to form functional p75. In the TBC of these knockout mice, examined as adults, patterns of cytochrome oxidase staining (which parallel those of p75-IR) appeared to be normal. In summary, during early development, p75 is widely expressed in the TBC during periods of active synaptogenesis and pattern formation, whereas in the adult, its expression is restricted to association with populations of primary sensory afferents. However, the absence of functional p75 in genetically altered mice does not appear to prevent primary afferent pattern formation.
Anat Rec 1999 04 01
PMID:Distribution of the low-affinity neurotrophin receptor (p75) in the developing trigeminal brainstem complex in the rat. 1020 62

Recently it has been observed that a subpopulation of gut endocrine cells in vertebrates express Trk-like proteins, suggesting that neurotrophins could regulate the synthesis and storage of amines and peptides of these cells. Nevertheless, the peptides and amines present in the endocrine cells that express Trks have not been characterized. In this study we used immunohistochemistry to investigate the occurrence of Trk-like proteins (TrkA-like, TrkB-like and TrkC-like) and the possible co-localization of these with peptides and/or biogenic amines in the endocrine cells of the stomach of three teleost (bass, gilt-head and scorpionfish). No TrkA-like immunoreactivity (IR) was detected in the stomach of these species, whereas TrkB-like IR and TrkC-like IR were observed in numerous cells of the gastric epithelium. TrkB-like immunoreactive cells were present in all three species examined, and were particularly abundant in the blind sac. Conversely, TrkC-like immunoreactive cells were found only in the bass stomach, apparently co-localized with TrkB-like IR. TrkB-like IR was found co-localized with somatostatin IR in scorpionfish, and with somatostatin and CGRP IR in gilt-head and bass. Gastric endocrine cells expressing 5-HT, glucagon, insulin, met-, leu-enkephalin, substance P, PYY, VIP, CCK, NPY, bombesin and motilin were unreactive for Trk-like proteins. The present results provide direct evidence for the occurrence of Trk-like neurotrophin receptor proteins in a subpopulation of the teleostean gastric endocrine cells and suggest that neurotrophins could regulate, as in neurons, the expression of some neuropeptides such as somatostatin and CGRP.
Anat Rec 1999 11 01
PMID:Co-localization of Trk neurotrophin receptors and regulatory peptides in the endocrine cells of the teleostean stomach. 1052 80

In addition to their well-known actions within the nervous system, neurotrophins and their receptors are involved in immune system functioning, as demonstrated by their wide distribution in lymphoid tissues and their in vitro actions on immunocompetent cells. Nevertheless, the in vivo roles of neurotrophin-receptor systems in lymphoid tissues, as well as the scope of their influence throughout development and adulthood, are yet to be clarified. In the present study, we used combined morphological and immunohistochemical techniques to investigate the presence and cellular localization of p75NTR, the pan-neurotrophin receptor protein, in rat spleen from newborns to aging individuals, and the structural and innervation changes in the spleens of p75NTR-deficient mice. In rats, p75NTR was expressed by splenic nerve fibers and dendritic cells in an age-regulated fashion, with maximal expression detected at 2 weeks. Consistently, the spleens of newborn mice lacking this receptor protein showed no signs of ingrowing sympathetic fibers, along with an absence of defined white pulp areas. The present findings suggest a prolonged role of p75NTR in the physiology of the spleen; at least during the embryonic development period, the receptor may be critical for correct innervation and compartmentalization processes to occur.
Anat Rec A Discov Mol Cell Evol Biol 2003 Feb
PMID:p75NTR in the spleen: age-dependent changes, effect of NGF and 4-methylcatechol treatment, and structural changes in p75NTR-deficient mice. 1252 87

Liver progenitor cells as well as hepatic stellate cells have neuroendocrine features. Progenitor cells express chromogranin-A and neural cell adhesion molecule, parathyroid hormone-related peptide, S-100 protein, neurotrophins, and neurotrophin receptors, while hepatic stellate cells express synaptophysin, glial fibrillary acidic protein, neural cell adhesion molecule, nestin, neurotrophins, and their receptors. This phenotype suggests that these cell types form a neuroendocrine compartment of the liver, which could be under the control of the central nervous system. We recently showed that the parasympathetic nervous system promotes progenitor cell expansion after liver injury, since selective vagotomy reduces the number of progenitor cells after chemical injury in the rat. Similarly, after transplantation, which surgically denervates the liver, human livers that develop hepatitis have fewer progenitor cells than native, fully innervated livers with similar degrees of liver injury. There is also accumulating experimental evidence linking the autonomic system, in particular the sympathetic nervous system (SNS), with the pathogenesis of cirrhosis and its complications. Recently, it has been shown that hepatic stellate cells themselves respond to neurotransmitters. Moreover, inhibition of the SNS reduced fibrosis in carbon tetrachloride-induced liver injury. In view of the denervated state of transplanted livers, it is very important to unravel the neural control mechanisms of regeneration and fibrogenesis. Moreover, since there is a shortage of donor organs, a better understanding of the mechanisms of regeneration could have therapeutic possibilities, which could even obviate the need for orthotopic liver transplantation.
Anat Rec A Discov Mol Cell Evol Biol 2004 Sep
PMID:Neuroregulation of the neuroendocrine compartment of the liver. 1538 10

Brain-derived neurotrophic factor and neurotrophin-4 are required for normal taste bud development. Although these neurotrophins normally function via the tyrosine kinase receptor, trkB, they also bind to the pan-neurotrophin receptor, p75. The goal of the present study was to determine whether the p75 receptor is required for the development or maintenance of a full complement of adult taste buds. Mice with p75 null mutations lose 34% of their circumvallate taste buds, 36% of their fungiform papillae, and 26% of their fungiform taste buds by adulthood. The reduction of taste buds in the adult circumvallate papilla was similar to that observed previously at postnatal day 7 (Fan et al. Brain Res Dev Brain Res 2004;150:23-39). Taken together, these findings indicate that the p75 receptor is critical for the development of a full complement of taste buds, but is not required for maintenance of circumvallate taste buds in adulthood. Immunolabeling for p75 was not observed in taste buds, indicating that p75 signaling influences taste bud number indirectly. Geniculate ganglion neurons, which provides innervation to fungiform taste buds, express the p75 receptor. Mice with p75 null mutations also have fewer neurons in the geniculate ganglion. Together, these results suggest that the p75 receptor is important for the survival of geniculate neurons and geniculate neuron survival is required for the development of a full complement of taste buds by adulthood.
Anat Rec A Discov Mol Cell Evol Biol 2006 Dec
PMID:Mice lacking the p75 receptor fail to acquire a normal complement of taste buds and geniculate ganglion neurons by adulthood. 1708 22

Morphological development of sensory structures in the laryngeal mucosa of postnatal rats was observed by use of immunohistochemistry for protein gene-product 9.5 (PGP9.5). Moreover, expression changes of high affinity neurotrophin receptors, TrkA, TrkB and TrkC, and low affinity neurotrophin receptor p75(NTR) were examined to elucidate the relationship to morphogenesis. Intraepithelial nerve endings and parent axons of the laminar endings with immunoreactivity for PGP9.5 have already appeared in the rat on embryonic day 18 (E18) as well as solitary chemoreceptor cells in the glottic cleft. According to neurotrophin receptors, TrkA immunoreactivity were observed on and after postnatal week 3 (3W) in the nervous sensory structures, that is, free nerve endings, laminar endings and sub- and intragemmal plexuses of the taste buds. In the laminar endings, TrkC immunoreactivity was also observed on and after 3W. According to the laryngeal sensory cells, the solitary chemoreceptor cells were immunoreactive to TrkA, TrkB, and TrkC on and after postnatal day 3 (P3). In the taste buds in arytenoid region, taste cells were immunoreactive for TrkA, TrkB, and TrkC on and after 3W, P14, and 3W, respectively. Immunoreactivity for p75(NTR) was observed on the surface of taste cells on and after P9. The results of the present study suggest that sensory structures in the laryngeal mucosa were developed on perinatal days to involve respiratory reflex, and that neurotrophin receptors may take part in the regulation and maintenance of sensory structures.
Anat Rec (Hoboken) 2011 Apr
PMID:Morphological development and expression of neurotrophin receptors in the laryngeal sensory corpuscles. 2137 Apr 91

Severe to profound deafness is most often secondary to a loss of or injury to cochlear mechanosensory cells, and there is often an associated loss of the peripheral auditory neural structures, specifically the spiral ganglion neurons and peripheral auditory fibers. Cochlear implantation is currently our best hearing rehabilitation strategy for severe to profound deafness. These implants work by directly electrically stimulating the remnant auditory neural structures within the deafened cochlea. When administered to the deafened cochlea in animal models, neurotrophins, specifically brain derived neurotrophic factor and neurotrophin-3, have been shown to dramatically improve spiral ganglion neuron survival and stimulate peripheral auditory fiber regrowth. In animal models, neurotrophins administered in combination with cochlear implantation has resulted in significant improvements in the electrophysiological and psychophysical measures of outcome. While further research must be done before these therapies can be applied clinically, neurotrophin therapies for the inner ear show great promise in enhancing CI outcomes and the treatment of hearing loss.
Anat Rec (Hoboken) 2012 Nov
PMID:The use of neurotrophin therapy in the inner ear to augment cochlear implantation outcomes. 2304 34

The spiral ganglion neurons (SGNs) are the afferent neurons of the cochlea, connecting the auditory sensory cells-hair cells-to the brainstem cochlear nuclei. The neurotrophins neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF) are expressed in the cochlea and both support SGN survival during development. These neurotrophins remain expressed in the postnatal cochlea and continue to play additional roles for SGNs, contributing to maintenance of hair cell-SGN synapses and regulating expression of ion channels, presynaptic and postsynaptic proteins, and SGN membrane electrical properties in a physiologically important spatial pattern. Remarkably, NT-3 and BDNF have different, even opposing, effects on SGN physiology despite the close similarity of their receptors TrkB and TrkC. Recent studies have also raised the possibility that precursor proneurotrophin forms of the neurotrophins play a role in responses to trauma in the cochlea, signaling through the proneurotrophin receptor p75(NTR) . Here, we review expression and function of neurotrophins and their p75(NTR) and Trk-family receptors in the cochlea. We focus, in particular, on neurotrophin functions other than support of SGN survival, including regulation of SGN neurite growth, synaptic and membrane physiology. These functions, unlike survival, are ones for which BDNF and NT-3 substantially differ in their effects. Signal transduction mechanisms of p75(NTR) and of Trk-family receptors are discussed, indicating how these lead to different responses, and we speculate on how BDNF and NT-3 can cause different phenotypic changes in SGNs. Because these complex signaling interactions remain incompletely understood, use of neurotrophins as therapeutic agents in the cochlea should be approached with caution.
Anat Rec (Hoboken) 2012 Nov
PMID:The Trk A, B, C's of neurotrophins in the cochlea. 2304 62


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