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LRIG1 Regulates Ontogeny of Smooth Muscle-Derived Subsets of Interstitial Cells of Cajal in Mice.
Kondo J, Powell AE, Wang Y, Musser MA, Southard-Smith EM, Franklin JL, Coffey RJ
(2015) Gastroenterology 149: 407-19.e8
MeSH Terms: Animals, Fluorescent Antibody Technique, Homozygote, Integrases, Interstitial Cells of Cajal, Intestine, Small, Membrane Glycoproteins, Mice, Mice, Knockout, Muscle, Smooth, Myenteric Plexus, Nerve Tissue Proteins, Recombination, Genetic, Submucous Plexus
Show Abstract · Added July 28, 2015
BACKGROUND & AIMS - Interstitial cells of Cajal (ICC) control intestinal smooth muscle contraction to regulate gut motility. ICC within the plane of the myenteric plexus (ICC-MY) arise from KIT-positive progenitor cells during mouse embryogenesis. However, little is known about the ontogeny of ICC associated with the deep muscular plexus (ICC-DMP) in the small intestine and ICC associated with the submucosal plexus (ICC-SMP) in the colon. Leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) marks intestinal epithelial stem cells, but the role of LRIG1 in nonepithelial intestinal cells has not been identified. We sought to determine the ontogeny of ICC-DMP and ICC-SMP, and whether LRIG1 has a role in their development.
METHODS - Lrig1-null mice (homozygous Lrig1-CreERT2) and wild-type mice were analyzed by immunofluorescence and transit assays. Transit was evaluated by passage of orally administered rhodamine B-conjugated dextran. Lrig1-CreERT2 mice or mice with CreERT2 under control of an inducible smooth muscle promoter (Myh11-CreERT2) were crossed with Rosa26-LSL-YFP mice for lineage tracing analysis.
RESULTS - In immunofluorescence assays, ICC-DMP and ICC-SMP were found to express LRIG1. Based on lineage tracing, ICC-DMP and ICC-SMP each arose from LRIG1-positive smooth muscle progenitors. In Lrig1-null mice, there was loss of staining for KIT in DMP and SMP regions, as well as for 2 additional ICC markers (anoctamin-1 and neurokinin 1 receptor). Lrig1-null mice had significant delays in small intestinal transit compared with control mice.
CONCLUSIONS - LRIG1 regulates the postnatal development of ICC-DMP and ICC-SMP from smooth muscle progenitors in mice. Slowed small intestinal transit observed in Lrig1-null mice may be due, at least in part, to loss of the ICC-DMP population.
Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
0 Communities
3 Members
0 Resources
14 MeSH Terms
Rapid high-amplitude circumferential slow wave propagation during normal gastric pacemaking and dysrhythmias.
O'Grady G, Du P, Paskaranandavadivel N, Angeli TR, Lammers WJ, Asirvatham SJ, Windsor JA, Farrugia G, Pullan AJ, Cheng LK
(2012) Neurogastroenterol Motil 24: e299-312
MeSH Terms: Animals, Electrophysiology, Female, Interstitial Cells of Cajal, Membrane Potentials, Models, Theoretical, Muscle, Smooth, Myoelectric Complex, Migrating, Stomach, Submucous Plexus, Swine
Show Abstract · Added April 26, 2016
BACKGROUND - Gastric slow waves propagate aborally as rings of excitation. Circumferential propagation does not normally occur, except at the pacemaker region. We hypothesized that (i) the unexplained high-velocity, high-amplitude activity associated with the pacemaker region is a consequence of circumferential propagation; (ii) rapid, high-amplitude circumferential propagation emerges during gastric dysrhythmias; (iii) the driving network conductance might switch between interstitial cells of Cajal myenteric plexus (ICC-MP) and circular interstitial cells of Cajal intramuscular (ICC-IM) during circumferential propagation; and (iv) extracellular amplitudes and velocities are correlated.
METHODS - An experimental-theoretical study was performed. High-resolution gastric mapping was performed in pigs during normal activation, pacing, and dysrhythmia. Activation profiles, velocities, and amplitudes were quantified. ICC pathways were theoretically evaluated in a bidomain model. Extracellular potentials were modeled as a function of membrane potentials.
KEY RESULTS - High-velocity, high-amplitude activation was only recorded in the pacemaker region when circumferential conduction occurred. Circumferential propagation accompanied dysrhythmia in 8/8 experiments was faster than longitudinal propagation (8.9 vs 6.9 mm s(-1) ; P = 0.004) and of higher amplitude (739 vs 528 μV; P = 0.007). Simulations predicted that ICC-MP could be the driving network during longitudinal propagation, whereas during ectopic pacemaking, ICC-IM could outpace and activate ICC-MP in the circumferential axis. Experimental and modeling data demonstrated a linear relationship between velocities and amplitudes (P < 0.001).
CONCLUSIONS & INFERENCES - The high-velocity and high-amplitude profile of the normal pacemaker region is due to localized circumferential propagation. Rapid circumferential propagation also emerges during a range of gastric dysrhythmias, elevating extracellular amplitudes and organizing transverse wavefronts. One possible explanation for these findings is bidirectional coupling between ICC-MP and circular ICC-IM networks.
© 2012 Blackwell Publishing Ltd.
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1 Members
0 Resources
11 MeSH Terms
It's about time: clock genes unveiled in the gut.
Scheving LA, Russell WE
(2007) Gastroenterology 133: 1373-6
MeSH Terms: ARNTL Transcription Factors, Animals, Basic Helix-Loop-Helix Transcription Factors, CLOCK Proteins, Cell Cycle Proteins, Circadian Rhythm, Colon, Cryptochromes, DNA-Binding Proteins, Epithelial Cells, Feeding Behavior, Flavoproteins, Gastrointestinal Tract, Gene Expression Regulation, Humans, Liver, Nuclear Proteins, Receptors, Cytoplasmic and Nuclear, Sodium-Hydrogen Exchanger 3, Sodium-Hydrogen Exchangers, Stomach, Submucous Plexus, Suprachiasmatic Nucleus, Trans-Activators, Transcription Factors
Added March 24, 2014
0 Communities
1 Members
0 Resources
25 MeSH Terms