The first intestinal motility patterns in fetal mice are not mediated by neurons or interstitial cells of Cajal

• Published in: The Journal of physiology 2010-04, Vol.588 (7), p.1153-1169
• Main Authors: Roberts, Rachael R., Ellis, Melina, Gwynne, Rachel M., Bergner, Annette J., Lewis, Martin D., Beckett, Elizabeth A., Bornstein, Joel C., Young, Heather M.
• Format: Article
• Language: English
• Subjects: Alimentary; Animals; Calcium Channels, L-Type - drug effects; Calcium Channels, L-Type - physiology; Cobalt - pharmacology; Colon - embryology; Colon - innervation; Colon - physiology; Duodenum - embryology; Duodenum - innervation; Duodenum - physiology; Female; Fetus - innervation; Fetus - physiology; Gastrointestinal Motility; Interstitial Cells of Cajal - drug effects; Interstitial Cells of Cajal - physiology; Male; Mice; Mice, Mutant Strains; Muscle Contraction - drug effects; Muscle Contraction - physiology; Myenteric Plexus - cytology; Myenteric Plexus - physiology; Neurons - physiology; Nicardipine - pharmacology; Proto-Oncogene Proteins c-kit - physiology; Tetrodotoxin - pharmacology
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2009.185421

In mature animals, neurons and interstitial cells of Cajal (ICC) are essential for organized intestinal motility. We investigated motility patterns, and the roles of neurons and myenteric ICC (ICC‐MP), in the duodenum and colon of developing mice in vitro. Spatiotemporal mapping revealed regular contractions that propagated in both directions from embryonic day (E)13.5 in the duodenum and E14.5 in the colon. The propagating contractions, which we termed ripples, were unaffected by tetrodotoxin and were present in the intestine of embryonic Ret null mutant mice, which lack enteric neurons. Neurally mediated motility patterns were first observed in the duodenum at E18.5. To examine the possible role of ICC‐MP, three approaches were used. First, intracellular recordings from the circular muscle of the duodenum did not detect slow wave activity at E16.5, but regular slow waves were observed in some preparations of E18.5 duodenum. Second, spatiotemporal mapping revealed ripples in the duodenum of E13.5 and E16.5 W/Wv embryos, which lack KIT+ ICC‐MP and slow waves. Third, KIT‐immunoreactive cells with the morphology of ICC‐MP were first observed at E18.5. Hence, ripples do not appear to be mediated by ICC‐MP and must be myogenic. Ripples in the duodenum and colon were abolished by cobalt chloride (1 mm). The L‐type Ca2+ channel antagonist nicardipine (2.5 μm) abolished ripples in the duodenum and reduced their frequency and size in the colon. Our findings demonstrate that prominent propagating contractions (ripples) are present in the duodenum and colon of fetal mice. Ripples are not mediated by neurons or ICC‐MP, but entry of extracellular Ca2+ through L‐type Ca2+ channels is essential. Thus, during development of the intestine, the first motor patterns to develop are myogenic. Organized movements of the intestine (motility) in adults require both neurons and cells called interstitial cells of Cajal. Although the fetus receives nutrition via the placenta, we show that intestinal motility begins during fetal stages in mice. However, at most fetal ages, intestinal motility is generated solely by muscle cells of the gut wall, and neurons and interstitial cells of Cajal do not play a role in gut motility until just prior to birth. These results are important for understanding motility disorders in premature infants.