MUTATION OF THE PROTOONCOGENE C-KIT BLOCKS DEVELOPMENT OF INTERSTITIAL-CELLS AND ELECTRICAL RHYTHMICITY IN MURINE INTESTINE

1. Interstitial cells of Cajal (ICs) have been proposed as pacemakers in the gastrointestinal tract. We studied the characteristics and dist ribution of ICs and electrical activity of small intestinal muscles fr om mice with mutations at the dominant-white spotting/c- kit (W) locus because the tyrosine kinase function of c-kit may be important in the development of the IC network. 2. W/W-V mutants (days 3-30 postpartum ) had few ICs in the myenteric plexus region compared with wild type ( +/+) siblings. The few ICs present were associated with neural element s and lay between myenteric ganglia and the longitudinal muscle layer. 3. Electrical recordings from intestinal muscle strips showed that el ectrical slow waves were always present in muscles of +/+ siblings, bu t were absent in W/W-V mice. 4. Muscles from W/W-V mice responded to s timulation of intrinsic nerves. Neural responses, attributed to the re lease of acetylcholine, nitric oxide and other unidentified transmitte rs, were recorded. 5. These findings are consistent with the hypothesi s that ICs are a critical element in the generation of electrical rhyt hmicity in intestinal muscles. The data also show that neural regulati on of gastrointestinal muscles can develop independently of the IC net work. 6. W locus mutants provide a powerful new model for studies of t he physiological role of ICs and the significance of electrical rhythm icity to normal gastrointestinal motility.