To test whether Notch1 signaling act as a key factor in ccRCC-development in vivo, we crossed the transgenic mouse line CALSL-NICD that conditionally confers ectopic expression of human NICD151, with mice carrying a floxed Vhl (Vhlfl/fl) allele52, and the Kap2-iCre mouse strain53, in which improved Cre (iCre) is driven by the androgen inducible and PTEC specific kidney androgen protein 2 (Kap2) promoter (Fig. 2A). Here, VHL is linked to nonpapillary renal cell carcinoma.