In a pedigree derived from a mouse treated with the mutagen ethylnitrosourea, a mutation has been identified that predisposes to spontaneous intestinal cancer. The mutant gene was found to be dominantly expressed and fully penetrant. Affected mice developed multiple adenomas throughout the entire intestinal tract at an early age.

Germ-line mutations of the APC gene are responsible for familial adenomatous polyposis (FAP), an autosomal dominantly inherited disease in humans. Patients with FAP develop multiple benign colorectal tumors. Recently, a mouse lineage that exhibits an autosomal dominantly inherited predisposition to multiple intestinal neoplasia (Min) was described. Linkage analysis showed that the murine homolog of the APC gene (mApc) was tightly linked to the Min locus. Sequence comparison of mApc between normal and Min-affected mice identified a nonsense mutation, which cosegregated with the Min phenotype. This mutation is analogous to those found in FAP kindreds and in sporadic colorectal cancers.

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. Min is a fully penetrant dominant mutation that leads to the development of multiple intestinal adenomas throughout the duodenal-to-colonic axis.Minl+ C57BL6/J mice have an average life-span of 120 d. Mufti-label immunocytochemical studies of these lesions demonstrate patches of differentiated enterocytes, and scattered enteroendocrine, goblet and Paneth cells . Expression of endogenous marker genes within these differentiated cells can be directly correlated with the position occupied by the adenoma along the duodenal-to-colonic axis and mirrors the regional differentiation of the normal gut epithelium . The presence of multiple lineages in adenomas together with their retention of spatial information suggests that tumorigenesis in Minl+ mice may be initiated in a multipotent stem cell normally located at the base of intestinal crypts . To study the time-dependent properties of these tumors, genetic conditions were T HE mouse intestinal epithelium undergoes perpetual renewal of its four principal terminally differentiated cell types: the polarized absorptive enterocyte, the mucus-producing goblet cell, a complex population of enteroendocrine cells, and the defensin/lysozyme containing Paneth cell which is thought to function as part ofthe biological barrier to bacterial translocation across the gut (reviewed in Gordon, 1989) . Renewal and differentiation are rapid, extraordinarily well organized in several spatial dimensions, and dependent upon multipotent stem cells that are functionally anchored at the base of intestinal crypts (Cheng and Leblond, 1974). In the adult small intestine, 6-10 crypts, each composed of -250 cells, surround each villus. ['H]Thymidine labeling studies indicate that 150 cells, located in the middle portion of each crypt, pass through the cell cycle every 12 h resulting in the generation of 300 new cells/ crypt/d (reviewed in Potten and Loefer, 1990). These cells undergo a bipolar migration . -12 cells emerge from each crypt per hour and are translocated in coherent vertical bands up the adjacent villus (Cheng and Leblond, 1974; Potten and Loefer, 1990;Schmidt et al., 1985b). Differentiation ofenterocytes, goblet and enteroendocrine cells occurs during this upward migration which is completed in 3 d when the sooner. These studies indicate that the Minl+ mouse is a powerful model system for analyzing the mechanisms that establish and maintain a balance between proliferation and differentiation in the continuously renewing gut epithelium and for an assessment of the multi-step hypothesis of intestinal neoplasia . cells are exfoliated into the gut lumen at the apical extrusion zone of the villus . Each villus contains a steady state level of -3,500 surface epithelial cells and sheds -1,400 cells/