DEVELOPMENT OF ELECTRICAL RHYTHMICITY IN THE MURINE GASTROINTESTINAL-TRACT IS SPECIFICALLY ENCODED IN THE TUNICA MUSCULARIS

1. Interstitial cells of Cajal (ICCs) have been identified as pacemake r cells in the gastrointestinal (GI) tracts of vertebrates. We have st udied the development of ICCs in pacemaker regions and the onset of el ectrical rhythmicity in the gastric antrum, small bowel and proximal c olon of the mouse. 2. ICCs, as detected by c-Kit immunofluorescence, w ere found during embryogenesis in regions of the GI tract that eventua lly become pacemaker areas. Prior to birth, these cells were organized into well-structured networks, and by the end of tile embryonic perio d the morphology of ICC networks in pacemaker regions appeared very si milar to that observed in adult animals. 3. Electrical rhythmicity was recorded prior to birth (by E18) in the proximal GI tract (stomach an d jejunum), and this activity developed to adult-like behaviour within a week after birth. In the ileum and proximal colon rhythmicity devel oped after birth, and adultlike characteristics were apparent within t he first week. 4. Post-junctional responses of smooth muscles to neura l inputs could be recorded at birth, and stimulation of intrinsic nerv es often led to oscillatory activity resembling slow waves for up to s everal minutes following brief stimuli. Nerve stimulation augmented sp ontaneous activity in the proximal portions of the GI tract and elicit ed rhythmic activity temporarily in quiescent tissues of the distal GI tract. 5. ICCs and rhythmicity developed in an apparently normal mann er in tissues isolated at birth and placed in organ culture. These dat a suggest that the tunica muscularis provides a suitable microenvironm ent for the development of ICCs and rhythmicity without the need for e xtrinsic stimuli. 6. Treatment of small intestinal tissues taken from embryos at E15 with neutralizing c-Kit antibodies abolished ICC develo pment and the organization of ICCs into networks that typically occurs during the late embryonic period. Treatment of muscles taken from new born animals with c-Kit antibodies blocked postnatal development of IC Cs, disrupted already established and functional ICC networks, and ren dered muscles electrically quiescent. 7. In summary, ICC networks deve lop in the pacemaker regions of the murine GI tract before birth. Deve lopment and organization of ICCs of the myenteric plexus region into n etworks precedes the development of electrical rhythmicity. Post-natal development of electrical rhythmicity is mainly characterized by enha ncement of the amplitude and frequency of slow waves. The development of ICCs and electrical rhythmicity persists in vitro. ICCs appear to b e necessary for the initiation of electrical rhythmicity. These findin gs provide further evidence for the pacemaker role of ICCs.