The Hedgehog (Hh) signalling pathway is essential for metazoan development and aberrant activation of the pathway is found in tumours. Mutations in Hh pathway components are found in several tumour types, including basal cell carcinoma (BCC) and medulloblastoma (MB). The outline of the Hh pathway is evolutionary conserved, with Patched (Ptch) as the Hh receptor and Smoothened (Smo) as the signal transducer that relays the signal into the cytoplasm to activate the transcription factors Ci/Gli, which regulate gene transcription and cellular responses leading to cell proliferation and/or differentiation. These studies focus on the function of Ptch1 and Suppressor of fused (Sufu), both negative regulators of Hh signalling. In paper I, we showed that genetic ablation of Sufu in mice results in embryonic lethality around embryonic day 9 with failure to close the neural tube. Sufu-/- embryos showed high Gli activity that was not repressable at the level of Smo. Sufu+/- mice develop jaw keratocysts and a skin phenotype with BCC-like lesions, alopecia, increased skin pigmenation, and abberant sebaceous gland morphology. Our data show that in contrast to the situation in Drosophila, Sufu has a central role in mammalian Hh signalling, and its loss-offunction leads to ligand-independent activation of the Hh pathway. In paper II, we have investigated the possibility that Sufu would modulate the phenotype of Ptch1+/- mice or vice-versa. We found that the frequency of MB was not altered in Sufu+/-Ptch+/- mice compared to Ptch1+/- mice. All MB in Ptch1+/- mice and all but one MB in Sufu+/-Ptch1+/- mice had lost expression of the Ptch1 wt allele, indicating that this is the critical genetic change leading to MB formation in these mice. Skin from Sufu+/-, Ptch1+/- and Sufu+/-Ptch1+/- mice developed BCClike epidermal lesions. The number of such lesions was increased in Sufu+/-Ptch1+/- mice compared to Sufu+/- and Ptch1+/- mice. Our data indicate a differential importance of Sufu and Ptch1 as tumour suppressors in MB versus the ...