Studying the consequences of immediate loss of gene function in the intestine: APC

The use of mouse models to study neoplasia is proving particularly powerful in dissecting the mechanisms underlying disease initiation and progression. However, the majority of these models have been somewhat limited in studying the very early effects of loss of gene function, as tumour initiation relies upon either constitutive loss of gene function or spontaneous somatic loss of function. We have therefore adopted a strategy of using an inducible Cre-lox-based system to analyse the effects of loss of gene function, the use of which is reviewed here for the intestinal tumour suppressor APC (adenomatous polyposis coli). Using this approach, we have conditionally and synchronously inactivated APC in virtually all the epithelial cells of the adult murine small intestine. After 5 days following induction of Cre-mediated recombination, mice show grossly altered crypt/villus architecture. Deficiency in APC perturbs migration, alters the normal programme of differentiation and results in increased proliferation and apoptosis. Microarray analysis reveals the transcriptome to be significantly altered; reflecting both gross phenotypic changes and changes in transcriptional activation. These findings demonstrate that APC is indeed the critical determinant of cell fate in the intestinal epithelium, explaining its role as the cellular ‘gatekeeper’ in preventing neoplasia.