C-KIT-DEPENDENT DEVELOPMENT OF INTERSTITIAL-CELLS AND ELECTRICAL-ACTIVITY IN THE MURINE GASTROINTESTINAL-TRACT

In vivo injection of a neutralizing, monoclonal antibody (ACK2) to the receptor tyrosine kinase (c-kit) disrupts the normal motility pattern s of the mouse small intestine. Immunohistochemical studies showed tha t cells expressing c-kit-like immunoreactivity (c-kit-LI) decreased in numbers in response to ACK2, but the identity of these cells is unkno wn, We investigated the identity and development of the cells that exp ress c-kit-LI in the mouse small intestine and colon. Cells in the reg ion of the myenteric plexus and deep muscular plexus of the small inte stine and in the subserosa, in the myenteric plexus region, within the circular and longitudinal muscle layers, and along the submucosal sur face of the circular muscle in the colon were labeled with ACK2. The d istribution of cells that express c-kit-LI was the same as that of int erstitial cells (ICs). In whole-mount preparations cells with c-kit-LI were interconnected, forming a network similar to the network formed by cells that stained with methylene blue, which has been used as a ma rker for ICs in the mouse gastrointestinal tract. Immunocytochemistry verified that ICs were labeled with ACK2. Multiple injections of anima ls with ACK2 between days 0 and 8 post partum (pp) caused a dramatic r eduction in the number of ICs compared to control animals. From an ult rastructural point of view, the proliferation and development appeared to be suppressed in some classes of ICs, while others displayed an al tered course of development. Functional studies showed that the decrea se in ICs was accompanied by a loss of electrical rhythmicity in the s mall intestine and reduced neural responses in the small bowel and col on. Morphological experiments showed that c-kit-positive cells are ICs , and physiological evidence reinforced the concept that ICs are invol ved in generation of rhythmicity and translation of neural inputs in g astrointestinal smooth muscles. Controlling the development of ICs pro vides a powerful new tool for the investigation of the physiological r ole of these cells.