Interstitial cells of Cajal (ICC) aroused much interest among neuroanatomists at the beginning of the century. These small cells, organized into networks, are intercalated between nerve fibers and muscle cells, and are now considered by many authors to be responsible for the pacemaker activity of the gut. Renewed interest in these cells arose recently when the receptor tyrosine kinase, c-kit, was shown to be associated with their functional activity. The embryonic origin of interstitial cells has remained a controversial issue ever since their discovery. Some authors consider them to be of neural or glial nature and thus of neural crest origin. Others consider them to be of fibroblastic or muscular nature. We have applied the quail-chick marker system to solve this problem. ICC were identified by means of a chicken-c-kit nucleic probe which cross-reacts with the quail c-kit gene product. We constructed chimeric bowels by grafting isotopically quail vagal neural crest into chick embryos at embryonic day 2 (E2). The enteric innervation of the chimeras was then of quail origin. In situ hybridization of the chimeric bowels showed that all the c-kit-positive cells were of the chick type, and therefore belonged to the gut mesenchyme and were not neural crest-derived cells. This observation was confirmed by culturing aneural chick guts on the chorio-allantoic membrane. Typical ICC, as defined at the EM level and by their expression of the c-kit receptor, developed in the gut wall in the complete absence of enteric innervation. One can conclude the ICC are of mesodermal origin and develop independently from enteric neurons with which they later establish anatomical and functional relations.

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