Targeted ablation of secretin-producing cells in transgenic mice reveals acommon differentiation pathway with multiple enteroendocrine cell lineagesin the small intestine

The four cell types of gut epithelium, enteroendocrine cells, enterocytes, Paneth cells and goblet cells, arise from a common totipotent stem cell loc ated in the mid portion of the intestinal gland, The secretin-producing (S) cell is one of at least ten cell types belonging to the diffuse neuroendoc rine system of the gut. We have examined the developmental relationship bet ween secretin cells and other enteroendocrine cell types by conditional abl ation of secretin cells in transgenic mice expressing herpes simplex virus 1 thymidine kinase (HSVTK), Ganciclovir-treated mice showed markedly increa sed numbers of apoptotic cells at the crypt-villus junction. Unexpectedly, ganciclovir treatment induced nearly complete ablation of enteroendocrine c ells expressing cholecystokinin and peptide YY/glucagon (L cells) as well a s secretin cells, suggesting a close developmental relationship between the se three cell types. In addition, ganciclovir reduced the number of enteroe ndocrine cells producing gastric inhibitory polypeptide, substance-P, somat ostatin and serotonin, During recovery from ganciclovir treatment, the ente roendocrine cells repopulated the intestine in normal numbers, suggesting t hat a common early endocrine progenitor was spared. Expression of BETA2, a basic helix-loop-helix protein essential for differentiation of secretin an d cholecystokinin cells was examined in the proximal small intestine. BETA2 expression was seen in all enteroendocrine cells and not seen in nonendocr ine cells. These results suggest that most small intestinal endocrine cells are developmentally related and that a close developmental relationship ex ists between secretin-producing S cells and cholecystokinin-producing and L type enteroendocrine cells. In addition, our work shows the existence of a multipotent endocrine-committed cell type and locates this hybrid multipot ent cell type to a region of the intestine populated by relatively immature cells.