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Background  The Ras and Notch signaling pathways are frequently activated during development to control many diverse cellular processes and are often dysregulated during tumorigenesis. To study the role of Notch and oncogenic Kras signaling in a progenitor cell population,  Pdx1-Cre  mice were utilized to generate conditional oncogenic  Kras G12D   mice with ablation of  Notch1  and/or  Notch2 .    Methodology/Principal Findings  Surprisingly, mice with activated  Kras G12D   and  Notch1  but not  Notch2  ablation developed skin papillomas progressing to squamous cell carcinoma providing evidence for  Pdx1  expression in the skin. Immunostaining and lineage tracing experiments indicate that PDX1 is present predominantly in the suprabasal layers of the epidermis and rarely in the basal layer. Further analysis of keratinocytes  in vitro  revealed differentiation-dependent expression of PDX1 in terminally differentiated keratinocytes. PDX1 expression was also increased during wound healing. Further analysis revealed that loss of Notch1 but not Notch2 is critical for skin tumor development. Reasons for this include distinct Notch expression with Notch1 in all layers and Notch2 in the suprabasal layer as well as distinctive p21 and β-catenin signaling inhibition capabilities.    Conclusions/Significance  Our results provide strong evidence for epidermal expression of Pdx1 as of yet not identified function. In addition, this finding may be relevant for research using  Pdx1-Cre  transgenic strains. Additionally, our study confirms distinctive expression and functions of Notch1 and Notch2 in the skin supporting the importance of careful dissection of the contribution of individual Notch receptors.

Identification of Epidermal Pdx1 Expression Discloses Different Roles of Notch1 and Notch2 in Murine KrasG12D-Induced Skin Carcinogenesis In Vivo