Apc1638T: a mouse model delineating critical domains of the adenomatous polyposis coli protein involved in tumorigenesis and development

The adenomatous polyposis coli (APC) gene is considered as the true gatekee per of colonic epithelial proliferation: It is mutated in the majority of c olorectal tumors, and mutations occur at early stages of tumor development in mouse and man. These mutant proteins lack most of the seven 20-amino-aci d repeats and all SAMP motifs that have been associated with down-regulatio n of intracellular beta-catenin levels. In addition, they lack the carboxy- terminal domains that bind to DLG, EB1, and microtubulin. APC also appears to be essential in development because homozygosity for mouse Ape mutations invariably results in early embryonic lethality. Here, we describe the gen eration of a mouse model carrying a targeted mutation at codon 1638 of the mouse Ape gene, Apc1638T, resulting in a truncated Ape protein encompassing three of the seven 20 amino acid repeats and one SAMP motif, but missing a ll of the carboxy-terminal domains thought to be associated with tumorigene sis. Surprisingly, homozygosity for the Apc1638T mutation is compatible wit h postnatal life. However, homozygous mutant animals are characterized by g rowth retardation, a reduced postnatal viability on the B6 genetic backgrou nd, the absence of preputial glands, and the formation of nipple-associated cysts. Most importantly, Apc(1638T/1638T) animals that survive to adulthoo d are tumor free. Although the full complement of Apc1638T is sufficient fo r proper beta-catenin signaling, dosage reductions of the truncated protein result in increasingly severe defects in beta-catenin regulation. The SAMP motif retained in Apc1638T also appears to be important for this function as shown by analysis of the Apc1572T protein in which its targeted deletion results in a further reduction in the ability of properly controlling beta -catenin/Tcf signaling. These results indicate that the association with DL G, EB1, and microtubulin is less critical for the maintenance of homeostasi s by APC than has been suggested previously, and that proper beta-catenin r egulation by APC appears to be required for normal embryonic development an d tumor suppression.