Current models of hair follicle development suggest that the establishment of a regular array of placodes in the surface epithelium in response to the first dermal message is achieved through the competing activities of molecules that promote or repress placode fate [24]. There is accumulating evidence that activation of the Wnt signaling pathway in the dermis may be involved in establishing the first dermal signal. Experimental activation of epithelial β-catenin signaling (by expression of N-terminal–truncated, constitutively stabilized forms of β-catenin or ectopic expression of Lef1) induces ectopic follicles in both mouse and chick skin [25–27]. Conversely, down-regulation of β-catenin signaling (through Lef1 knock-out, ectopic expression of Wnt inhibitor Dkk1 or conditional deletion of β-catenin in epidermis) results in loss of vibrissae and some pelage follicles in mice [28–30]. Our finding that K14-driven Apc loss in embryonic ectoderm resulted in irregularly spaced and often tightly clustered abnormal hair placode initiation and follicle morphogenesis (Figures 4F, 5B, 5D, and 5F) as well as in the development of multiple tooth buds (Figure 4O and 4P), is in line with the effects seen in activation of epithelial β-catenin signaling during placode formation, indicating the role of Apc in specification of embryonic ectodermal stem cells to produce a hair follicle. Given the role of Apc in down-regulation of β-catenin, loss of Apc would inevitably lead to altered expression of β-catenin in ectodermal cells during the hair placode formation, giving rise to aberrant follicular growth throughout the embryonic epidermis, including the footpads, where normally hairless (Figure 5B, 5D, 5F, and 5H). Of interest are the phenotypic similarities and differences between our KA mutant mice and the previously described K14-ΔN87βcat transgenic mice expressing stable β-catenin under the control of K14 promoter [25] and K14-Lef1 transgenic mice [27]. Surprisingly, our mutant mice shared more similarities with the K14-Lef1 mice than the K14-ΔN87βcat transgenic mice. For example, the KA mutant mice displayed the disoriented and short, curly whiskers seen in K14-Lef1but not in K14-ΔN87βcat transgenic mice. In addition, KA mutant mice displayed a disorganized hair coat beginning with the emergence of neonatal hairs, similar to that observed in K14-Lef1 mice, whereas in K14-ΔN87βcat mice, embryonic hair follicle morphogenesis was unaffected and other skin changes only emerged postnatally. The reason for this difference could be attributed to one or all of three possible contributing factors. (1) Although the K14 promoter itself is known to initiate the expression at E9.5 and elevated dramatically by E13.5–E14.5 [19,31], many factors could influence the expression of promoter/transgene construct in transgenic mice. One of the most important considerations has to do with the integration site of the transgene in the mouse genome. Depending on the location of integration, the transcriptional activity of even the same transgene could vary considerably. It is possible that the apparent lack of ΔN87βcat function in embryogenesis could be due to the delayed or weak expression of the K14-ΔN87βcat transgene compared to the intrinsic promoter. In contrast, Cre-mediated recombination is seen in E13.5 skin of K14-cre transgenic mice used in this study [16] and K14-cre–mediated truncation of the Apc gene is likely to have occurred by then, in time for the second wave of hair follicle morphgenesis. (2) Another important fact is that in the aforementioned transgenic model the overexpression of transgene is confined to the basal cells of the epidermis and the ORS of hair follicles, where the K14 promoter is active. The expression of transgene is hence transient and stops once K14-expressing cells terminally differentiate. In contrast, in our model, K14-cre–mediated deletion of Apc would result in Apc mutation not only in K14 promoter active cells, but remain so in all cell layers that derived from the K14 promoter active progenitors. These derivatives include the suprabasal epidermis and the entire epithelium of the hair follicle. Stabilization of β-catenin in a broader population of cells could account for some of the phenotypic differences. However, we did not detect any elevated β-catenin expression in either K1- or K6-positive differentiated cells in postnatal mutant skin. This indicates that despite the absence of Apc and potential stabilization of β-catenin in derivatives of K14-expressing progenitors, elevated β-catenin expression, and subsequent cell fate determination may only take place in basal cells. (3) We cannot exclude the possibility that given the multifunctional properties of Apc, disruption of its functions other than down-regulation of β-catenin may also have contributed to the observed overt phenotype.