Abstract
The tumor suppressor gene Apc (adenomatous polyposis coli) is a member of the Wnt signaling pathway that is involved in development and tumorigenesis. Heterozygous knockout mice for Apc have a tumor predisposition phenotype and homozygosity leads to embryonic lethality. To understand the role of Apc in development we generated a floxed allele. These mice were mated with a strain carrying Cre recombinase under the control of the human Keratin 14 (K14) promoter, which is active in basal cells of epidermis and other stratified epithelia. Mice homozygous for the floxed allele that also carry the K14-cre transgene were viable but had stunted growth and died before weaning. Histological and immunochemical examinations revealed that K14-cre–mediated Apc loss resulted in aberrant growth in many ectodermally derived squamous epithelia, including hair follicles, teeth, and oral and corneal epithelia. In addition, squamous metaplasia was observed in various epithelial-derived tissues, including the thymus. The aberrant growth of hair follicles and other appendages as well as the thymic abnormalities in K14-cre; ApcCKO/CKO mice suggest the Apc gene is crucial in embryonic cells to specify epithelial cell fates in organs that require epithelial–mesenchymal interactions for their development.
Highlights
Adenomatous polyposis coli (APC) is a member of the Wnt signaling pathway and one of its known functions is to regulate the levels of b-catenin
Apc is implicated in the Wnt signaling pathway that is involved both in development and tumorigenesis
Human germline mutations in APC cause familial adenomatous polypois (FAP) [4,5], which is characterized by hundreds of adenomatous colorectal polyps, with an almost inevitable progression to colorectal cancer in the third and fourth decades of life
Summary
Adenomatous polyposis coli (APC) is a member of the Wnt signaling pathway and one of its known functions is to regulate the levels of b-catenin. APC interacts with a multitude of other cellular proteins, including axin-2 (AXIN2), plakoglobin (JUP), Asef (ARHGEF4), kinesin superfamily–associated protein 3 (KIFAP3), EB1 (MAPRE1), microtubules, and the human homolog of Drosophila discs large (DLG1). These interactions suggest that APC can potentially regulate many cellular functions, including intercellular adhesion, cytoskeletal organization, regulation of plakoglobin levels, regulation of the cell cycle and apoptosis, orientation of asymmetric stem cell division, and control of cell polarization [2,3]. In addition to colorectal neoplams, these individuals can develop extracolonic symptoms, among which are upper gastrointestinal tract polyps, congenital hypertrophy of the retinal pigment epithelium, desmoid tumors, disorders of the maxillary and skeletal bones, and dental abnormalities [6], suggesting the importance of APC gene functions in these organ systems
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