In this study, we observed that K14-driven loss of Apc resulted in a small thymus with severe squamous metaplasia leading to the formation of numerous pyogranuloma and loss of proper meshwork structure for thymocyte maturation, rendering the mice athymic. Previous studies have shown that in normal adult thymus K14 expression is found together with K5 in the stellate medullary TECs, but not in association with K5+ TECs in the cortex or at the cortico-medullary junction. In addition, it has been demonstrated that K14+ TECs do not coexpress K8; hence, there are two distinct medullary subsets, namely a K8−K14+ stellate subset and a K8+K14− globular subset [32]. In agreement with the previous results, in P3 normal thymus K14 expression was restricted to stellate medullary TECs (Figure 6D), whereas K8 expression was found throughout the TECs (unpublished data). We could not clarify whether these two keratins were coexpressed in the same TECs without double-staining. There were individual differences among mutants and these were prominently reflected in the histological abnormalities of the thymus at P3, but as the older surviving mutants all showed the same histopathologies of the thymus, the mutant thymi eventually seem to result in the same fate. It is unclear when K14-cre induction actually takes place in the mutant thymus, but as the population of cells showing a strong nuclear β-catenin staining as well as the cells expressing K14 were small and thymic epithelial compartments still existed in a mild P3 mutant thymus (Figure 6E and 6F), it seems that initial differentiation to medullary and cortical TECs and thymocyte colonization have already taken place prior to the major effects of K14-driven Apc loss. However, cells with nuclear β-catenin and K8+K14+ double-positive epithelial cells increased subsequently, associated with active proliferation in the latter group of cells and loss of TEC compartments. With age, β-catenin expression pattern became more diffuse and fewer epithelial cells showed nuclear localization but K8+K14+ cells remained, forming concentric structures of epithelial cells filled with hard keratin deposits and infiltrated with vast number of neutrophils and macrophages. Only a few epithelial cells were dividing and hardly any thymocytes were present by this time. These results suggest that with the deletion of Apc in TECs, stabililization and nuclear localization of β-catenin took place and subsequently these cells differentiated into keratinocytes that expressed both K14 and K8, similar to the basal cells of the skin, instead of TEC subsets. The expansion and differentiation of these keratinocytes lead to loss of proper thymic epithelial compartments and in turn produced and deposited the hard keratins that consequently caused vast amount of neutrophils and macrophages to infiltrate the thymus. These aberrant epithelial structures eventually have overtaken the whole of the thymus and driven out the colonized thymocytes. K14-driven loss of Apc and subsequent constitutive expression of β-catenin in TECs have therefore misdirected them to wrong epithelial cell fate, not allowing proper differentiation to either cortical or medullary TECs, which is essential for normal thymocyte development. This is not only evident from the lack of dividing thymocytes in the mutant thymus by P13, but also by the differential expression pattern of keratins, which were more skin-like than TEC-like. The importance of Apc function in thymic development has been demonstrated by thymocyte-specific loss of Apc by crossing a different strain of Apc conditional mice and LckCre transgenic mice [33]. Here, by K14-driven TEC-specific loss of Apc, we have demonstrated its importance in thymus development not only in thymocytes but also in TECs.