Pdx1 Is Expressed in the Skin Figure 5. Phenotype of K5;N1ko and K5;N2ko mice. A: Notch1 is expressed in all layers of the adult skin whereas Notch2 is expressed only in the suprabasal layer as assessed using immunohistochemical staining and Notch1-GFP and Notch2LacZ reporter mice. B: Gross phenotype of K5;N1ko, K5;N2ko and WT mice at 4 weeks of age (left). Spontaneous skin tumors (white arrows) and hyperplastic opaque corneas (black arrowhead) start to develop in 9 months old K5;N1ko mice (middle and right). C: Skin histopathologies of K5;N1ko mice include epidermal cyst (asterisk), hair follicle malformation (black arrowhead, left), skin tumors (middle), hyperplasia of the cornea (black arrows, right). D: HE stain shows morphology and thickness (indicated by scale lines) of WT, K5;N1ko, K5;N2ko epidermis (left panel). Immunohistochemical staining reveals ubiquitous expression of active b-catenin in K5;N1ko (black arrows) comparing to WT and K5;N2ko mice epidermis (right panel). E: The thickness of K5;N1ko epidermis is significantly reduced compared to K5;N2ko and WT. The scale bars represent 50 mm. doi:10.1371/journal.pone.0013578.g005 Notch1 and Notch2 play different roles in skin tumorigenesis Different Notch receptors have often distinct expression patterns, ligand preferences and discrete downstream signaling. Although different Notch receptors can compensate each other e.g. in pancreas development [48], individual Notch receptors commonly have distinct functions in development [49], tumor- igenesis [46,50–52] or tissue regeneration [53]. The result of this study points to differences in expression pattern and distinctive cellular effectors as main cause of the diverse Notch1 and Notch2 knockout phenotypes. First, we found that Notch1 and Notch2 PLoS ONE | www.plosone.org 8 October 2010 | Volume 5 | Issue 10 | e13578