Target determination of neurotransmitter phenotype in sympathetic neurons

Schotzinger, Robert J.; Yin, Xinghuan; Landis, Story C.

doi:10.1002/neu.480250605

Cited by 97 publications

(52 citation statements)

References 110 publications

(139 reference statements)

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“…Target tissue regulation of neuronal phenotype has been demonstrated in sympathetic neurons whose adrenergic or cholinergic neurotransmitter fate can be modified in vivo and in vitro by altering environmental cues (Patterson and Nawa, 1993;Schotzinger and Landis, 1994). Thus, sympathetic neurons can alter their neurotransmitter to match target tissue effectors.…”

Section: Discussionmentioning

confidence: 99%

The Generation of Neuronal Heterogeneity in a Rat Sensory Ganglion

Hall

Hickman

et al. 1997

J. Neurosci.

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Adult sensory neurons differ chemically, morphologically, and functionally, but the factors that generate their diversity remain unclear. For example, neuropeptides are generally found in small neurons, whereas abundant neurofilament is common in large neurons. Neurons containing the neuropeptides calcitonin gene-related peptide (CGRP) or substance P were quantified using immunohistochemistry in rat lumbar dorsal root ganglion (DRG) at times before and after sensory neurons contact central and peripheral targets in vivo. No neurons in the newly formed DRG expressed neuropeptide or neuropeptide mRNA, but neuropeptides were detectable about the time that axons connect with peripheral targets. To determine the requirement for target in neuropeptide regulation, embryonic DRG neurons were isolated at times before central and peripheral connections had formed, placed in culture, and immunocytochemically assayed for CGRP and substance P. Cultured neurons expressed neuropeptides with a time course and in proportions similar to those in vivo. Thus, some neurons in the embryonic DRG seem to be intrinsically specified to later express CGRP and substance P. The percentage of CGRP-immunoreactive neurons was not changed by cell density, non-neuronal cells, neurotrophins in addition to nerve growth factor (NGF), or antibody inactivation of neurotrophin-3 in the presence of NGF. To test the role of extrinsic cues on CGRP expression, DRG neurons were co-cultured with potential target tissues. Coculture with a rat epidermal or smooth muscle cell line increased the proportion of CGRP-containing neurons, whereas primary skeletal muscle and 3T3 cells had no effects. Thus, multiple appropriate sensory neuron phenotypes arise in a regulated fashion in cultured neurons isolated before target connections have formed, and some candidate target tissues can modulate that intrinsic expression pattern. Key words: neuropeptides; substance P; calcitonin generelated peptide; neurofilament; nociceptive; sensory ganglion; target tissue; skin; neurotrophinA striking feature of the adult vertebrate sensory nervous system is the diversity of neuronal cell types that perform together to maintain homeostasis and convey information about the environment. During development, specific neurons must be generated in appropriate locations and connect discretely to both peripheral targets and the CNS for functional integrity. Thus, it is important to understand not only how the phenotype is generated but also how neurons match targets. This study examines the developmental regulation of sensory neurons containing calcitonin generelated peptide (CGRP) that predominantly contact visceral and cutaneous peripheral target end organs in vivo.Adult rat sensory neurons can express neuromodulatory neuropeptides, but the factors that regulate their initial expression remain unknown. Cutaneous afferents appear in rat proximal hindlimb on embryonic days 14 -15 (E14 -E15) and in skin of distal toes at E16 -E17 (Reynolds et al

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Section: Discussionmentioning

confidence: 99%

The Generation of Neuronal Heterogeneity in a Rat Sensory Ganglion

Hall

Hickman

et al. 1997

J. Neurosci.

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“…Although the majority of sympathetic neurons express norepinephrine as their neurotransmitter, a small percentage of neurons, particularly those that innervate the sweat glands, change transmitter and neuropeptide phenotype during normal development to produce acetylcholine and vasoactive intestinal peptide (VIP) (31,32). Neuropoietic cytokines, including CNTF, LIF, OSM, IL-11, and CT-1, induce the same phenotypic changes of the neurotransmitter and neuropeptide expression pattern in sympathetic neurons in vitro as sweat glands do in vivo (31)(32)(33). In contrast, only minor effects have been reported for IL-6 on these neurons (33,34).…”

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confidence: 99%

Sympathetic neurons can produce and respond to interleukin 6

März

Cheng

Gadient

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

291

176

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Neuronal expression of cytokines is an area of active investigation in the contexts of development, disease, and normal neural function. Although cultured rat sympathetic neurons respond very weakly to exogenous interleukin 6 (IL-6), we find that addition of soluble IL-6 receptor (sIL-6R) and IL-6 enhances neuronal survival in the absence of nerve growth factor. Neutralizing monoclonal antibodies against IL-6 block these effects. Addition of IL-6 and sIL-6R also induces a subset of neuropeptide and transmitter synthetic enzyme mRNAs identical to that demonstrated for leukemia inhibitory factor, ciliary neurotrophic factor, and oncostatin M. Both of these effects are duplicated by addition of a highly active fusion protein of sIL-6R and IL-6, covalently linked by a f lexible peptide chain, which is designated H-IL-6. In addition, we show that sympathetic neurons produce IL-6. In situ hybridization indicates a neuronal localization of IL-6 mRNA in superior cervical ganglia, and bioactive IL-6 protein is detected in ganglion culture supernatants. Interestingly, the IL-6 produced by sympathetic neurons does not lead to survival of these cells in culture unless sIL-6R is added. Thus, sympathetic neurons can produce IL-6 and may respond to it in an autocrine͞paracrine manner if sIL-6R is present. Moreover, the prior findings of sIL-6R in serum and inf lammatory f luids now have added interest in the context of neuroimmune interactions.

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“…2 In culture all embryonic ciliary neurons are rescued by a select group of CNTF-like neurotrophic factors but not by members of the neurotrophin family (20,22). Also, CNTF has trophic activities for motor, sensory, sympathetic, and hippocampal neurons, regulates acetylcholine receptors on autonomic neurons, and regulates neurotransmitter expression in cultured sympathetic and central nervous system neurons (23)(24)(25)(26)(27)(28)(29).…”

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confidence: 99%

Ciliary Neurotrophic Factor Stimulates the Phosphorylation of Two Forms of STAT3 in Chick Ciliary Ganglion Neurons

Wishingrad¹,

Koshlukova²,

Halvorsen

1997

Journal of Biological Chemistry

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Ciliary neurotrophic factor (CNTF) is a neuropoietic cytokine that was identified, purified, and cloned based on its neurotrophic activity on cultured chick ciliary ganglion neurons. The molecular mechanisms by which CNTF elicits its effects on these neurons are unknown. We have previously identified functional receptors for CNTF on ciliary ganglion neurons and demonstrated the CNTF-specific tyrosine phosphorylation of an approximately 90-kDa protein. Here we show that CNTF induced the rapid tyrosine phosphorylation and nuclear accumulation of this protein and identify it as an avian form of the transcription factor, STAT3. Identification was confirmed by its recognition with two distinct anti-STAT3 antibodies and the lack of binding to antibodies against STAT1, -2, -4, -5, or -6. The phosphorylation was stable for up to 2 h but required the continued presence of CNTF. CNTF also induced the tyrosine phosphorylation of a similar protein in cultured chick dorsal root ganglion and retinal neurons. In addition, we identify a second, 100-kDa form of STAT3 that appears in response to CNTF. Unlike previous reports, utilizing mammalian cell lines that detected a slower migrating form of STAT3 resulting from H7-sensitive protein phosphorylation, H7 did not prevent the appearance of the 100-kDa form in ciliary neurons. Thus, the 100-kDa avian protein may represent a novel form of CNTF-inducible STAT3. Ciliary neurotrophic factor (CNTF)1 is a cytokine that shows activity toward a variety of cell types in the nervous system. However, the molecular mechanisms for these effects have not been clearly elucidated in defined neuronal populations. CNTF belongs to a family of neuropoietic cytokines, which display a high degree of redundancy in their biological activities, have structural similarity, share receptor subunits and signal transduction pathways, and yet are capable of generating unique cellular responses as well (1, 2). The known receptor complexes for CNTF, leukemia inhibitory factor, oncostatin M, cardiotrophin-1, and interleukin-6 and -11, include gp130 as a ␤-receptor component, and all except interleukin-6 and -11 share the leukemia inhibitory factor ␤-receptor component (3-7). CNTF and interleukin-6 and -11 also utilize unique ligand-binding ␣ subunits (1,8,9). Receptor activation by CNTF-related cytokines results in dimerization of the ␤-receptor components and activation of receptor-associated tyrosine kinases of the Jak family. Jaks or other cytoplasmic kinases phosphorylate tyrosine on the cytokine receptor components that selectively bind cytoplasmic transcription factors of the STAT (signal transducers and activators of transcription) family (10). In this model, established primarily from cell lines, STAT proteins are directly tyrosine-phosphorylated by Jaks and then dimerize and translocate to the cell nucleus and regulate gene transcription (11-13). There are at least six members of the STAT family, and the selection and activation of a particular STAT is dependent on receptor substrate-specifying motifs (1...

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Target determination of neurotransmitter phenotype in sympathetic neurons

Cited by 97 publications

References 110 publications

The Generation of Neuronal Heterogeneity in a Rat Sensory Ganglion

The Generation of Neuronal Heterogeneity in a Rat Sensory Ganglion

Sympathetic neurons can produce and respond to interleukin 6

Ciliary Neurotrophic Factor Stimulates the Phosphorylation of Two Forms of STAT3 in Chick Ciliary Ganglion Neurons

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