Purification and partial characterization of a cholinergic neuronal differentiation factor.

Fukada, Keiko

doi:10.1073/pnas.82.24.8795

Cited by 154 publications

(82 citation statements)

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“…Our observation that the factor stimulating somatostatin expression is soluble and secreted from choroid cells is consistent with other studies in which soluble factors have been shown to influence neurotransmitter expression (Patterson and Chun, 1977;Kessler et al, 1984;Fukada, 1985;Zurn and Do, 1988;Denis-Donini, 1989;Iacovitti et al, 1989;Martinou et al, 1989;Nawa and Patterson, 1990;Nawa and Sah, 1990) and differs from membrane-contact-mediated factors that also have been reported (Hawrot, 1980;Black, 1985, 1986;Kessler et al, 1986;Gray and Tuttle, 1987;Wong and Kessler, 1987;Adler et al, 1989). Preliminary charcterization of size suggests that the somatostatin-stimulating activity (SSA) is a macromolecule and not a small metabolite (Zurn and Do, 1988) or a neuropeptide (Denis-Donini, 1989).…”

Section: Discussionsupporting

confidence: 79%

“…For example, during development of the neonatal rat, a subpopulation of sympathetic neurons switches its neurotransmitter phenotype from adrenergic to cholinergic after contacting its targets (Yodlowski et al, 1984;Leblanc and Landis, 1986;Schotzinger and Landis, 1988). A similar adreneregicto-cholinergic change in neurotransmitter expression can also be induced in vitro in response to a glycoprotein purified from medium conditioned by heart cells (Fukada, 1985; see also Yamamori et al, 1989).…”

mentioning

confidence: 97%

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Stimulation of somatostatin expression in developing ciliary ganglion neurons by cells of the choroid layer

Coulombe

Nishi

1991

J. Neurosci.

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An important component of neuronal development is the matching of neurotransmitter expression with the appropriate target cell. We have examined how peptide transmitter expression is controlled in a simple model system, the avian ciliary ganglion (CG). This parasympathetic ganglion contains 2 distinct types of neurons: choroid neurons, which project to vasculature in the eye's choroid layer and use somatostatin as a co-transmitter with ACh, and ciliary neurons, which innervate the ciliary body and iris and use ACh but no known peptide co-transmitter. We have found that the earliest developmental stage in which neurons with somatostatinlike immunoreactivity (SOM-IR) are consistently found in vivo is stage 30 (embryonic day 6.5), a time shortly after the extension of neurites to targets in the eye's choroid layer. In cell culture, CG neurons expressed SOM-IR in co-culture with choroid cells, but not when cultured with striated muscle myotubes or with ganglion non-neuronal cells. No significant differences in neuronal survival or in ChAT activity were observed under these different co-culture conditions, which suggests that somatostatin expression is independently regulated. The stimulation of somatostatin expression was also specific in that other neuropeptides commonly found in autonomic neurons [neuropeptide Y (NPY), substance P (SP), vasoactive intestinal polypeptide (VIP)] were not induced in the presence of choroid cells. The ability to stimulate SOM-IR was not contact dependent because a macromolecule of greater than or equal to 10 kDa in choroid-conditioned medium (ChCM) was found to stimulate somatostatin expression in a dosage-dependent fashion. The somatostatin-stimulating activity induced SOM-IR in more than 90% of CG neurons, as well as in retrogradely labeled ciliary neurons, which would not normally express SOM-IR. Thus, the expression of somatostatin in cultured CG neurons is regulated by a macromolecule produced by cells in the choroid layer, a target normally innervated in vivo by CG neurons expressing somatostatin.

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Section: Discussionsupporting

confidence: 79%

mentioning

confidence: 97%

Stimulation of somatostatin expression in developing ciliary ganglion neurons by cells of the choroid layer

Coulombe

Nishi

1991

J. Neurosci.

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“…Previous studies have established that leukemia inhibitory factor (LIF), a member of the IL-6 cytokine family, can induce cultured sympathetic neurons to switch neurotransmitters, from NE to Ach (8). Fukada purified a cholinergic differentiation factor from cultured rat heart cells that can induce neurotransmitter switching from NE to Ach in cultured sympathetic neurons (9,10), and Yamamori confirmed that this factor was identical to LIF (11). LIF can induce neurotransmitter switching in vitro and in vivo.…”

Section: Introductionmentioning

confidence: 80%

Heart failure causes cholinergic transdifferentiation of cardiac sympathetic nerves via gp130-signaling cytokines in rodents

Kanazawa¹,

Ieda²,

Kimura³

et al. 2010

J. Clin. Invest.

128

118

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Although several cytokines and neurotrophic factors induce sympathetic neurons to transdifferentiate into cholinergic neurons in vitro, the physiological and pathophysiological roles of this remain unknown. During congestive heart failure (CHF), sympathetic neural tone is upregulated, but there is a paradoxical reduction in norepinephrine synthesis and reuptake in the cardiac sympathetic nervous system (SNS). Here we examined whether cholinergic transdifferentiation can occur in the cardiac SNS in rodent models of CHF and investigated the underlying molecular mechanism(s) using genetically modified mice. We used Dahl salt-sensitive rats to model CHF and found that, upon CHF induction, the cardiac SNS clearly acquired cholinergic characteristics. Of the various cholinergic differentiation factors, leukemia inhibitory factor (LIF) and cardiotrophin-1 were strongly upregulated in the ventricles of rats with CHF. Further, LIF and cardiotrophin-1 secreted from cultured failing rat cardiomyocytes induced cholinergic transdifferentiation in cultured sympathetic neurons, and this process was reversed by siRNAs targeting Lif and cardiotrophin-1. Consistent with the data in rats, heart-specific overexpression of LIF in mice caused cholinergic transdifferentiation in the cardiac SNS. Further, SNS-specific targeting of the gene encoding the gp130 subunit of the receptor for LIF and cardiotrophin-1 in mice prevented CHF-induced cholinergic transdifferentiation. Cholinergic transdifferentiation was also observed in the cardiac SNS of autopsied patients with CHF. Thus, CHF causes target-dependent cholinergic transdifferentiation of the cardiac SNS via gp130-signaling cytokines secreted from the failing myocardium. IntroductionCardiac function is tightly controlled by the balance between the sympathetic nervous system (SNS) and the parasympathetic nervous system (PNS). The SNS produces norepinephrine (NE) and increases the heart rate, conduction velocity, and myocardial contraction and relaxation, while the PNS produces acetylcholine (Ach) that reduces cardiac performance. In congestive heart failure (CHF), sympathetic neural tone is upregulated, and excess SNS activation leads to pathophysiological effects, such as myocardial damage, decline of cardiac function, and lethal arrhythmia (1, 2), and also causes depletion of cardiac NE content (3). This depletion of NE in CHF has been considered to be the result of excess NE secretion, disturbance of NE reuptake, and loss of noradrenergic nerve terminals (4, 5). However, we recently reported that the attenuation of NE in CHF was caused by downregulation of NE synthesis, concomitant with the reduced NE reuptake (6). However, the molecular mechanisms underlying the reduction in catecholaminergic characteristics of cardiac SNS in CHF remain poorly understood.

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“…We therefore shed some light on the pathological significance of these findings in the failing heart, on the basis of in vitro studies showing that the addition of LIF to cultured sympathetic neurons induces cholinergic differentiation ( Figure 4). 148,149 Although the precise mechanism underlying cholinergic differentiation in cardiac sympathetic neurons remains largely unknown, Apostolova et al 150 provided evidence that the chromatin architecture protein, Satb2, which is induced downstream of the gp130 cytokines, could control the neurotransmitter switch in sweat gland-innervated neurons. This finding raised the possibility that an epigenetic modification is essential for sympathetic plasticity induced by target-derived humoral factors.…”

Section: Interleukin-6 Family Cytokinesmentioning

confidence: 99%

Development, Maturation, and Transdifferentiation of Cardiac Sympathetic Nerves

Kimura

Ieda

Fukuda

2012

Circulation Research

147

123

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Abstract:The heart is electrically and mechanically controlled as a syncytium by the autonomic nervous system. The cardiac nervous system comprises the sympathetic, parasympathetic, and sensory nervous systems that together regulate heart function on demand. Sympathetic electric activation was initially considered the main regulator of cardiac function; however, modern molecular biotechnological approaches have provided a new dimension to our understanding of the mechanisms controlling the cardiac nervous system. The heart is extensively innervated, although the innervation density is not uniform within the heart, being high in the subepicardium and the special conduction system. We and others showed previously that the balance between neural chemoattractants and chemorepellents determine cardiac nervous development, with both factors expressed in heart. Nerve growth factor is a potent chemoattractant synthesized by cardiomyocytes, whereas Sema3a is a neural chemorepellent expressed specifically in the subendocardium. Disruption of this wellorganized molecular balance and innervation density can induce sudden cardiac death due to lethal arrhythmias. In diseased hearts, various causes and mechanisms underlie cardiac sympathetic abnormalities, although their detailed pathology and significance remain contentious. We reported that cardiac sympathetic rejuvenation occurs in cardiac hypertrophy and, moreover, interleukin-6 cytokines secreted from the failing myocardium induce cholinergic transdifferentiation of the cardiac sympathetic system via a gp130 signaling pathway, affecting cardiac performance and prognosis. In this review, we summarize the molecular mechanisms involved in sympathetic development, maturation, and transdifferentiation, and propose their investigation as new therapeutic targets for heart disease. (Circ Res. 2012;110:325-336.) Key Words: cardiac sympathetic nervous system Ⅲ cardiac innervation patterning Ⅲ nerve growth factor Ⅲ cardiac rejuvenation Ⅲ cholinergic transdifferentiation Ⅲ IL-6 cytokines H eart tissue is extensively innervated via the autonomic nervous system, which comprises sympathetic and parasympathetic nerves. The cardiac sympathetic nervous system (SNS) uses norepinephrine (NE) as a neurotransmitter and increases the heart rate (chronotropic) and conduction velocity (dromotropic), as well as myocardial contraction (inotropic) and relaxation (lusitrophic). Sympathetic innervation density, which is highest in the subepicardium and central conduction system, is stringently regulated in the heart. 1 Regional differences in sympathetic innervation correspond to different areas of influence over cardiac function that cooperate to effectively control cardiac performance. Despite the clinical importance of cardiac innervation, little is known about the developmental and regulatory mechanisms underlying sympathetic innervation patterning.Cardiac innervation density is altered in pathological hearts, such as after myocardial infarction (MI), 2 in which the cardiac nerves undergo Walleria...

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Purification and partial characterization of a cholinergic neuronal differentiation factor.

Cited by 154 publications

References 56 publications

Stimulation of somatostatin expression in developing ciliary ganglion neurons by cells of the choroid layer

Stimulation of somatostatin expression in developing ciliary ganglion neurons by cells of the choroid layer

Heart failure causes cholinergic transdifferentiation of cardiac sympathetic nerves via gp130-signaling cytokines in rodents

Development, Maturation, and Transdifferentiation of Cardiac Sympathetic Nerves

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