Impaired development of interstitial cells and intestinal electrical rhythmicity in steel mutants

Abstract

Electrical rhythmicity in the gastrointestinal tract may originate in interstitial cells of Cajal (IC). Development of IC in the small intestine is linked to signaling via the tyrosine kinase receptor, c-kit. IC express c-kit protein, and disruption of c-kit signaling causes breakdown in IC networks and loss of slow waves. We tested whether mutations in steel factor, the ligand for c-kit, affect the development of IC networks. IC were found in the region of the myenteric plexus (IC-MY) in mice with steel mutations (i.e., Sl/Sld) at 5-10 days postpartum, but these cells formed an abnormal network. IC-MY were not observed in adult Sl/Sld animals. IC in the deep muscular plexus (IC-DMP) appeared normal in Sl/Sld animals. Electrical slow waves, normally present in the small intestine, were absent in Sl/Sld animals (10-30 days postpartum). Neural inputs were intact in Sl/Sld animals. Steel factor appears important for the development of certain classes of IC, and IC-MY appear to be involved in the generation of electrical rhythmicity in the small intestine.

Ascending contraction and descending relaxation in the distal colon of mice lacking interstitial cells of Cajal

“…The importance of ICC-IM in e.j.ps and contraction was also reported in the gastric fundus (Ward et al, 2000;Beckett et al, 2002). An important role of ICC-DMP in i.j.ps and e.j.ps was also suggested in the small intestine (Ward et al, 1995). Recently, we studied the association of ICC with mechanical responses in the mouse small intestine and postulated that ICC-MY have an essential role in inducing nitric oxide-mediated NANC relaxation of longitudinal muscle of the mouse ileum, and that ICC-MY also partly participate in EFS-induced contraction .…”

“…From the results obtained in W/W V and its wild type mice, ICC-MY were postulated to be important for inducing slow waves, but not i.j.ps in the ileum (Ward et al, 1994). Also in steel mutant and its wild type mice, ICC-MY were important for the slow waves, but not for EFS-induced e.j.ps and i.j.ps in the small intestine (Ward et al, 1995). ICC-MY were also suggested to be important for inducing slow waves in the gastric antrum (Burns et al, 1996).…”

Kit‐like immunoreactivity in the zebrafish gastrointestinal tract reveals putative ICC

“…Coordinated contractions, which are better organized and contribute to propulsive motility movements, develop gradually between 5 and 7 dpf, consistent with the time course of appearance of Kit immunoreactivity (personal observation). The role of ICC on intestinal transit has been well characterized in the mouse model and mutant mice lacking ICC exhibit spontaneous but poorly organized contractions and delayed intestinal transit (Torihashi et al, , 1997Ward et al, 1995). The poorly organized contractions in early zebrafish development are, therefore, similar to the ICC-deficient mutant mouse model.…”

Local presentation of Steel factor increases expression of c-kit immunoreactive interstitial cells of Cajal in culture

“…Separation of these isoforms occurs in the spontaneous Steel-Dickie (Sl d ) mutant mouse that exclusively expresses soluble SF, possibly providing an indication for the role of membrane-bound SF (2). The Sl/Sl d mouse does not display a spontaneous, rhythmic electrical slow wave, and ICC are not present in the myenteric plexus (34). These observations suggest that membrane-bound SF provides an essential role for the development and/or maintenance of ICC-MY.…”

“…ICC function as pacemaker cells in the gastrointestinal tract and may also modulate enteric neurotransmission (15,28,29). Spontaneous mutations at the white spotting locus, which encodes the c-kit receptor or the Steel locus, which encodes SF, are associated with disruption of the ICC network located at the myenteric plexus region (ICC-MY) of the small intestine and the functional loss of the spontaneous electrical slow wave and contractile activity (23,24,34,35). SF activation of c-kit is also necessary to maintain ICC, because the administration of neutralizing c-kit antibody results in the subsequent disappearance of ICC (21,30).…”