Exogenous Serotonin Regulates Proliferation of Interstitial Cells of Cajal in Mouse Jejunum Through 5-HT2B Receptors

Wouters, Mira M.; Gibbons, Simon J.; Roeder, Jaime L.; Distad, M. A.; Ou, Yijun; Strege, Peter R.; Szurszewski, Joseph H.; Farrugia, Gianrico

doi:10.1053/j.gastro.2007.06.017

Cited by 81 publications

(84 citation statements)

References 67 publications

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“…A role for 5-HT 2B receptors in cell differentiation and proliferation has been shown in various cell types and species including mouse enteric neurons, hepatocytes, mouse cardiomyocytes, and retinal cells in Xenopus (3)(4)(5)(6)(7)38). We demonstrated previously that activation of the 5-HT 2B receptor on murine ICC induces proliferation of ICC (9).…”

Section: Discussionmentioning

confidence: 82%

“…5-Hydroxytryptamine (5-HT, 2 serotonin) is well established as a neurotransmitter and a paracrine factor with over 90% of 5-HT produced by the gastrointestinal tract (1,2). There is now substantial evidence that, together with these established functions, 5-HT is involved in the control of cell proliferation through various 5-HT receptors, in particular the 5-hydroxytryptamine receptor 2B (5-HT 2B (3)(4)(5)(6)(7)(8)(9)). The 5-HT 2B receptor is G q/11 protein-coupled.…”

mentioning

confidence: 99%

“…Recently it was demonstrated that activation of the 5-HT 2B receptor also induces proliferation of neurons, retinal cells (3,4), hepatocytes (5), osteoblasts (8), and interstitial cells of Cajal (ICC) (9). ICC express the 5-HT 2B receptor, and activation by 5-HT induces proliferation of ICC (9). ICC are specialized, mesoderm-derived mesenchymal cells in the gastrointestinal tract.…”

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confidence: 99%

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Protein Kinase Cγ Mediates Regulation of Proliferation by the Serotonin 5-Hydroxytryptamine Receptor 2B

Wouters

Roeder

Tharayil

et al. 2009

Journal of Biological Chemistry

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Tight control of cell proliferation is essential to maintain organ size and function. Proliferation needs to be tightly regulated to maintain a critical mass of a particular cell type while preventing dysplasia or malignancy. Cell proliferation is regulated by a complex interaction between extrinsic and intrinsic factors. Extrinsic factors usually signal through cell surface receptors such as various growth factor receptors. 5-Hydroxytryptamine (5-HT, 2 serotonin) is well established as a neurotransmitter and a paracrine factor with over 90% of 5-HT produced by the gastrointestinal tract (1, 2). There is now substantial evidence that, together with these established functions, 5-HT is involved in the control of cell proliferation through various 5-HT receptors, in particular the 5-hydroxytryptamine receptor 2B (5-HT 2B (3-9)). The 5-HT 2B receptor is G q/11 protein-coupled. Activation of the 5-HT 2B receptor regulates cardiac function, smooth muscle contractility, vascular physiology, and mood control. Recently it was demonstrated that activation of the 5-HT 2B receptor also induces proliferation of neurons, retinal cells (3, 4), hepatocytes (5), osteoblasts (8), and interstitial cells of Cajal (ICC) (9). ICC express the 5-HT 2B receptor, and activation by 5-HT induces proliferation of ICC (9). ICC are specialized, mesoderm-derived mesenchymal cells in the gastrointestinal tract. Their best known function is the generation of slow waves (10), but they also conduct and amplify neuronal signals (11, 12), release carbon monoxide to set the intestinal smooth muscle membrane potential gradient (13), and act as mechanosensors (14, 15). Loss of ICC has been associated with pathological conditions such as gastroparesis (16 -18), infantile pyloric stenosis (19, 20), pseudo-obstruction (21, 22), and slow transit constipation (23), whereas increased proliferation of ICC or their precursors is associated with gastrointestinal stromal tumors (24).The mechanisms by which activation of the 5-HT 2B receptor results in increased proliferation are not well understood. In cultured cardiomyocytes, stimulation of the 5-HT 2B receptor activated both phosphatidylinositol 3-kinase (PI3Ј-K)/Akt and ERK1/2/mitogen-activated protein kinase (MAPK) signaling pathways to protect cardiomyocytes from apoptosis (25). On * This work was supported, in whole or in part, by National Institutes of Health Grants DK52766 and DK57061. □ S The on-line version of this article (available at http://www.jbc.org) contains supplemental 2 The abbreviations used are: 5-HT, 5-hydroxytryptamine, serotonin; 5-HT 2B , 5-hydroxytryptamine receptor 2B; Gö 6976, 12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo(

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Section: Discussionmentioning

confidence: 82%

mentioning

confidence: 99%

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confidence: 99%

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Protein Kinase Cγ Mediates Regulation of Proliferation by the Serotonin 5-Hydroxytryptamine Receptor 2B

Wouters

Roeder

Tharayil

et al. 2009

Journal of Biological Chemistry

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“…These data support and extend the previous analyses on these models using cell counts and volume computations [19,29], with more detailed structural and statistical evidence. Although Ano1 regulates ICC proliferation [29], alternative mechanisms of proliferation such as Kit [35] and serotonin [19,27] may compensate in the Ano1 KO model, resulting in structurally normal ICC networks.…”

Section: Discussionmentioning

confidence: 99%

“…This dataset contained 23 wild-type (WT) and 23 5-HT 2B serotonin receptor KO jejunal ICC network images from 4-week-old mice ( figure 2a,b). ICC express 5-HT 2B receptors, and stimulation with 5-HT (serotonin) increases ICC proliferation and numbers [27]. It has also been demonstrated that a lack of 5-HT 2B receptors decrease ICC proliferation, numbers and network volume [19].…”

Section: Interstitial Cell Of Cajal Network Imaging Data 221 Imagimentioning

confidence: 99%

Numerical metrics for automated quantification of interstitial cell of Cajal network structural properties

Gao

O’Grady

et al. 2013

J. R. Soc. Interface.

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Depletion of interstitial cells of Cajal (ICC) networks is known to occur in several gastrointestinal motility disorders. Although confocal microscopy can effectively image and visualize the spatial distribution of ICC networks, current descriptors of ICC depletion are limited to cell numbers and volume computations. Spatial changes in ICC network structural properties have not been quantified. Given that ICC generate electrical signals, the organization of a network may also affect physiology. In this study, six numerical metrics were formulated to automatically determine complex ICC network structural properties from confocal images: density, thickness, hole size, contact ratio, connectivity and anisotropy. These metrics were validated and applied in proof-of-concept studies to quantitatively determine jejunal ICC network changes in mouse models with decreased (5-HT 2B receptor knockout (KO)) and normal (Ano1 KO) ICC numbers, and during post-natal network maturation. Results revealed a novel remodelling phenomenon occurring during ICC depletion, namely a spatial rearrangement of ICC and the preferential longitudinal alignment. In the post-natal networks, an apparent pruning of the ICC network was demonstrated. The metrics developed here enabled the first detailed quantitative analyses of structural changes that may occur in ICC networks during depletion and development.

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Role of cilia in normal pancreas function and in diseased states

Diiorio

Rittenhouse

Bortell

et al. 2014

Birth Defects Research Pt C

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Primary cilia play an essential role in modulating signaling cascades that shape cellular responses to environmental cues to maintain proper tissue development. Mutations in primary cilium proteins have been linked to several rare developmental disorders, collectively known as ciliopathies. Together with other disorders associated with dysfunctional cilia/centrosomes, affected individuals have increased risk of developing metabolic syndrome, neurologic disorders, and diabetes. In pancreatic tissues, cilia are found exclusively in islet and ductal cells where they play an essential role in pancreatic tissue organization. Their absence or disorganization leads to pancreatic duct abnormalities, acinar cell loss, polarity defects, and dysregulated insulin secretion. Cilia in pancreatic tissues are hubs for cellular signaling. Many signaling components, such as Hh, Notch, and Wnt, localize to pancreatic primary cilia and are necessary for proper development of pancreatic epithelium and β-cell morphogenesis. Receptors for neuroendocrine hormones, such as Somatostatin Receptor 3, also localize to the cilium and may play a more direct role in controlling insulin secretion due to somatostatin's inhibitory function. Finally, unique calcium signaling, which is at the heart of β-cell function, also occurs in primary cilia. Whereas voltage-gated calcium channels trigger insulin secretion and serve a variety of homeostatic functions in β-cells, transient receptor potential channels regulate calcium levels within the cilium that may serve as a feedback mechanism, regulating insulin secretion. This review article summarizes our current understanding of the role of primary cilia in normal pancreas function and in the diseased state.

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Exogenous Serotonin Regulates Proliferation of Interstitial Cells of Cajal in Mouse Jejunum Through 5-HT2B Receptors

Cited by 81 publications

References 67 publications

Protein Kinase Cγ Mediates Regulation of Proliferation by the Serotonin 5-Hydroxytryptamine Receptor 2B

Protein Kinase Cγ Mediates Regulation of Proliferation by the Serotonin 5-Hydroxytryptamine Receptor 2B

Numerical metrics for automated quantification of interstitial cell of Cajal network structural properties

Role of cilia in normal pancreas function and in diseased states

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